Skip to main content

Advertisement

Log in

Chemoresistance Mechanisms in Non-Small Cell Lung Cancer—Opportunities for Drug Repurposing

  • Review Article
  • Published:
Applied Biochemistry and Biotechnology Aims and scope Submit manuscript

Abstract

Globally, lung cancer contributes significantly to the public health burden–associated mortality. As this form of cancer is insidious in nature, there is an inevitable diagnostic delay leading to chronic tumor development. Non-small cell lung cancer (NSCLC) constitutes 80–85% of all lung cancer cases, making this neoplasia form a prevalent subset of lung carcinoma. One of the most vital aspects for proper diagnosis, prognosis, and adequate therapy is the precise classification of non-small cell lung cancer based on biomarker expression profiling. This form of biomarker profiling has provided opportunities for improvements in patient stratification, mechanistic insights, and probable druggable targets. However, numerous patients have exhibited numerous toxic side effects, tumor relapse, and development of therapy-based chemoresistance. As a result of these exacting situations, there is a dire need for efficient and effective new cancer therapeutics. De novo drug development approach is a costly and tedious endeavor, with an increased attrition rate, attributed, in part, to toxicity-related issues. Drug repurposing, on the other hand, when combined with computer-assisted systems biology approach, provides alternatives to the discovery of new, efficacious, and safe drugs. Therefore, in this review, we focus on a comparison of the conventional therapy-based chemoresistance mechanisms with the repurposed anti-cancer drugs from three different classes—anti-parasitic, anti-depressants, and anti-psychotics for cancer treatment with a primary focus on NSCLC therapeutics. Certainly, amalgamating these novel therapeutic approaches with that of the conventional drug regimen in NSCLC-affected patients will possibly complement/synergize the existing therapeutic modalities. This approach has tremendous translational significance, since it can combat drug resistance and cytotoxicity-based side effects and provides a relatively new strategy for possible application in therapy of individuals with NSCLC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Division of Cancer Prevention and Control, & Centers for Disease Control and Prevention. (2021). Lung cancer | CDC. Retrieved March 15, 2021, from https://www.cdc.gov/cancer/lung/

  2. Niu, F. Y., Zhou, Q., Yang, J. J., Zhong, W. Z., Chen, Z. H., Deng, W., … Wu, Y. L. (2016). Distribution and prognosis of uncommon metastases from non-small cell lung cancer. BMC Cancer, 16(1), 1. https://doi.org/10.1186/s12885-016-2169-5

  3. WHO. (2021). Cancer. Retrieved March 15, 2021, from https://www.who.int/news-room/fact-sheets/detail/cancer

  4. Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 71(3), 209–249. https://doi.org/10.3322/CAAC.21660

    Article  PubMed  Google Scholar 

  5. NCI. (2020). Lung and bronchus cancer — Cancer stat facts. Retrieved March 16, 2021, from https://seer.cancer.gov/statfacts/html/lungb.html

  6. Maurie Markman. (2021). Types of lung cancer: Common, rare, aggressive and more | CTCA. CTCA. Retrieved March 16, 2021, from https://www.cancercenter.com/cancer-types/lung-cancer/types

  7. American Cancer Society. (2019). What is lung cancer? | Types of lung cancer. Retrieved March 16, 2021, from https://www.cancer.org/cancer/lung-cancer/about/what-is.html

  8. Subramanian, J., & Govindan, R. (2007). Lung cancer in never smokers: A review. Journal of Clinical Oncology, 25(5), 561–570. https://doi.org/10.1200/JCO.2006.06.8015

    Article  PubMed  Google Scholar 

  9. Kenfield, S. A., Wei, E. K., Stampfer, M. J., Rosner, B. A., & Colditz, G. A. (2008). Comparison of aspects of smoking among the four histological types of lung cancer. Tobacco Control, 17(3), 198–204. https://doi.org/10.1136/TC.2007.022582

    Article  CAS  PubMed  Google Scholar 

  10. Goldblum, J. R., Lamps, L. W., McKenney, J., & Myers, J. L. (2017). Rosai and Ackerman’s surgical pathology. Elsevier Health Sciences, 11th ed.,. Retrieved April 18, 2021, from https://books.google.co.in/books?hl=en&lr=&id=-7ZEDwAAQBAJ&oi=fnd&pg=PP1&dq=Goldblum+JR,+Lamps+LW,+McKenney+J,+%26+Myers+JL.+(2017).+Rosai+and+Ackerman%E2%80%99s+Surgical+Pathology.+Elsevier+Health+Sciences,+11th+ed&ots=w3sQv7jXSy&sig=2bWZ9SNuJrmdpXtMexnBNAPypcM&redir_esc=y#v=onepage&q=Goldblum%20JR%2C%20Lamps%20LW%2C%20McKenney%20J%2C%20%26%20Myers%20JL.%20(2017).%20Rosai%20and%20Ackerman%E2%80%99s%20Surgical%20Pathology.%20Elsevier%20Health%20Sciences%2C%2011th%20ed&f=false

  11. Alexandrov, L. B., Nik-Zainal, S., Wedge, D. C., Aparicio, S. A. J. R., Behjati, S., Biankin, A. v., … Stratton, M. R. (2013). Erratum: Signatures of mutational processes in human cancer (Nature (2013) 500 (415–421) https://doi.org/10.1038/nature12477). Nature, 502(7470), 258. https://doi.org/10.1038/NATURE12666

  12. Reya, T., Morrison, S. J., Clarke, M. F., & Weissman, I. L. (2001). Stem cells, cancer, and cancer stem cells. Nature, 414(6859), 105–111. https://doi.org/10.1038/35102167

    Article  CAS  PubMed  Google Scholar 

  13. Clarke, M. F., Dick, J. E., Dirks, P. B., Eaves, C. J., Jamieson, C. H. M., Jones, D. L., … Wahl, G. M. (2006). Cancer stem cells-Perspectives on current status and future directions: AACR Workshop on Cancer Stem Cells. Cancer Research, 66(19), 9339–44. https://doi.org/10.1158/0008-5472.CAN-06-3126

  14. Horn, L., & Sandler, A. B. (2009). Angiogenesis in the treatment of non-small cell lung cancer. Proceedings of the American Thoracic Society, 6(2), 206–217. https://doi.org/10.1513/PATS.200807-066LC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. de Wit, S., Rossi, E., Weber, S., Tamminga, M., Manicone, M., Swennenhuis, J. F., … Groen, H. J. M. (2019). Single tube liquid biopsy for advanced non-small cell lung cancer. International Journal of Cancer, 144(12), 3127–3137. https://doi.org/10.1002/IJC.32056

  16. Kunda, N. K. (2020). Antimicrobial peptides as novel therapeutics for non-small cell lung cancer. Drug Discovery Today, 25(1), 238–247. https://doi.org/10.1016/J.DRUDIS.2019.11.012

    Article  CAS  PubMed  Google Scholar 

  17. Padinharayil, H., Alappat, R. R., Joy, L. M., Anilkumar, K. V., Wilson, C. M., George, A., … Sathiyamoorthi, E. (2022). Advances in the lung cancer immunotherapy approaches. Vaccines, 10(11), 1963.

  18. Fatrekar, A. P., Morajkar, R., Krishnan, S., Dusane, A., Madhyastha, H., & Vernekar, A. A. (2021). Delineating the role of tailored gold nanostructures at the biointerface. ACS Applied Bio Materials, 4(12), 8172–8191. https://doi.org/10.1021/ACSABM.1C00998/ASSET/IMAGES/MEDIUM/MT1C00998_0008.GIF

    Article  CAS  PubMed  Google Scholar 

  19. Indrakumar, J., Sankar, S., Madhyastha, H., & Muthukaliannan, G. K. (2022). Progressive application of marine biomaterials in targeted cancer nanotherapeutics. Current Pharmaceutical Design, 28(41), 3337–3350. https://doi.org/10.2174/1381612828666220422091611

    Article  CAS  PubMed  Google Scholar 

  20. Gomathi, A., Alagumuthu, M., Jgs, P. K., Madhyastha, H., Jayaraj, R., & Gothandam, K. M. (2022). Apoptosis inducing metabolite from marine mangrove actinobacteria VITGAP173. Anti-cancer Agents in Medicinal Chemistry, 22. https://doi.org/10.2174/1871520622666220523155905

  21. Zhou, J., Kang, Y., Chen, L., Wang, H., Liu, J., Zeng, S., & Yu, L. (2020). The drug-resistance mechanisms of five platinum-based antitumor agents. Frontiers in Pharmacology, 11, 343. https://doi.org/10.3389/FPHAR.2020.00343/BIBTEX

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang, X., Zhang, H., & Chen, X. (2019). Drug resistance and combating drug resistance in cancer. Cancer Drug Resistance, (2), 141–60. https://doi.org/10.20517/cdr.2019.10

  23. Sharma, P., Mehta, M., Dhanjal, D. S., Kaur, S., Gupta, G., Singh, H., … Satija, S. (2019). Emerging trends in the novel drug delivery approaches for the treatment of lung cancer. Chemico-Biological Interactions, 309, 108720. https://doi.org/10.1016/J.CBI.2019.06.033

  24. Pushpakom, S., Iorio, F., Eyers, P. A., Escott, K. J., Hopper, S., Wells, A., … Pirmohamed, M. (2018). Drug repurposing: Progress, challenges and recommendations. Nature Reviews Drug Discovery, 18(1), 41–58. https://doi.org/10.1038/nrd.2018.168

  25. Fu, L., Jin, W., Zhang, J., Zhu, L., Lu, J., Zhen, Y., … Yu, H. (2022). Repurposing non-oncology small-molecule drugs to improve cancer therapy: Current situation and future directions. Acta Pharmaceutica Sinica B, 12(2), 532–557. https://doi.org/10.1016/J.APSB.2021.09.006

  26. Ashburn, T. T., & Thor, K. B. (2004). Drug repositioning: Identifying and developing new uses for existing drugs. Nature Reviews Drug Discovery, 3(8), 673–683. https://doi.org/10.1038/nrd1468

    Article  CAS  PubMed  Google Scholar 

  27. Jourdan, J. P., Bureau, R., Rochais, C., & Dallemagne, P. (2020). Drug repositioning: A brief overview. Journal of Pharmacy and Pharmacology, 72(9), 1145–1151. https://doi.org/10.1111/JPHP.13273

    Article  CAS  PubMed  Google Scholar 

  28. Pantziarka, P., Bouche, G., Meheus, L., Sukhatme, V., & Sukhatme, V. P. (2014). The Repurposing Drugs in Oncology (ReDO) Project. ecancermedicalscience, 8(1). https://doi.org/10.3332/ECANCER.2014.442

  29. Würth, R., Thellung, S., Bajetto, A., Mazzanti, M., Florio, T., & Barbieri, F. (2016). Drug-repositioning opportunities for cancer therapy: Novel molecular targets for known compounds. Drug Discovery Today, 21(1), 190–199. https://doi.org/10.1016/J.DRUDIS.2015.09.017

    Article  PubMed  Google Scholar 

  30. Mizugaki, H., Sakakibara-Konishi, J., Kikuchi, J., Moriya, J., Hatanaka, K. C., Kikuchi, E., … Nishimura, M. (2014). CD133 expression: A potential prognostic marker for non-small cell lung cancers. International Journal of Clinical Oncology, 19(2), 254–259. https://doi.org/10.1007/S10147-013-0541-X/TABLES/2

  31. Obermayr, E., Koppensteiner, N., Heinzl, N., Schuster, E., Holzer, B., Fabikan, H., … Zeillinger, R. (2021). Cancer stem cell-like circulating tumor cells are prognostic in non-small cell lung cancer. Journal of Personalized Medicine, 11(11), 1225. https://doi.org/10.3390/JPM11111225/S1

  32. Hase, T., Sato, M., Yoshida, K., Girard, L., Takeyama, Y., Horio, M., … Hasegawa, Y. (2011). Pivotal role of epithelial cell adhesion molecule in the survival of lung cancer cells. Cancer Science, 102(8), 1493–1500. https://doi.org/10.1111/J.1349-7006.2011.01973.X

  33. ZhenDe Z, Yun Song Li, Chong Yu Su, Xu Cheng, Shi Jie Zhou, Yi Han, … Feng Wang. (2021). Expression level of epithelial cell adhesion molecule (EpCAM) of circulating tumor cells (CTCs) of patients with NSCLC as an early indicator to monitor the effects of postoperative adjuvant chemotherapy. Translationa Cancer Research, 10(7), 3299–3305. https://doi.org/10.21037/tcr-21-205

  34. Leung, E. L. H., Fiscus, R. R., Tung, J. W., Tin, V. P. C., Cheng, L. C., Sihoe, A. D. L., … Wong, M. P. (2010). Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties. PLOS ONE, 5(11), e14062. https://doi.org/10.1371/JOURNAL.PONE.0014062

  35. Zhang, W. C., Ng, S. C., Yang, H., Rai, A., Umashankar, S., Ma, S., … Lim, B. (2012). Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell, 148(1–2), 259–272. https://doi.org/10.1016/J.CELL.2011.11.050

  36. Tachezy, M., Zander, H., Wolters-Eisfeld, G., Müller, J., Wicklein, D., Gebauer, F., … Bockhorn, M. (2014). Activated leukocyte cell adhesion molecule (CD166): An “inert” cancer stem cell marker for non-small cell lung cancer ? Stem Cells, 32(6), 1429–1436. https://doi.org/10.1002/STEM.1665

  37. Yan, X., Luo, H., Zhou, X., Zhu, B., Wang, Y., & Bian, X. (2013). Identification of CD90 as a marker for lung cancer stem cells in A549 and H446 cell lines. Oncology Reports, 30(6), 2733–2740. https://doi.org/10.3892/OR.2013.2784/HTML

    Article  CAS  PubMed  Google Scholar 

  38. Zhang, X., Tian, T., Sun, W., Liu, C., & Fang, X. (2017). Bmi-1 overexpression as an efficient prognostic marker in patients with nonsmall cell lung cancer. Medicine, 96(26). https://doi.org/10.1097/MD.0000000000007346

  39. Shen, H. T., Chien, P. J., Chen, S. H., Sheu, G. T., Jan, M. S., Wang, B. Y., & Chang, W. W. (2020). BMI1-mediated pemetrexed resistance in non-small cell lung cancer cells is associated with increased SP1 activation and cancer stemness. Cancers, 12(8), 2069. https://doi.org/10.3390/CANCERS12082069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Debruin, E. J., Hughes, M. R., Sina, C., Liu, A., Cait, J., Jian, Z., … McNagny, K. M. (2014). Podocalyxin regulates murine lung vascular permeability by altering endothelial cell adhesion. PLOS ONE, 9(10), e108881. https://doi.org/10.1371/JOURNAL.PONE.0108881

  41. Chen, M. J., Gao, X. J., Xu, L. N., Liu, T. F., Liu, X. H., & Liu, L. X. (2014). Ezrin is required for epithelial-mesenchymal transition induced by TGF-β1 in A549 cells. International Journal of Oncology, 45(4), 1515–1522. https://doi.org/10.3892/IJO.2014.2554/HTML

    Article  CAS  PubMed  Google Scholar 

  42. Kusumoto, H., Shintani, Y., Kanzaki, R., Kawamura, T., Funaki, S., Minami, M., … Okumura, M. (2017). Podocalyxin influences malignant potential by controlling epithelial–mesenchymal transition in lung adenocarcinoma. Cancer Science, 108(3), 528–535. https://doi.org/10.1111/CAS.13142

  43. Lu, J., Guo, H., Gao, B., Zhang, Y., Lin, Q., Shi, J., … Liu, J. (2018). Prognostic value of urokinase plasminogen activator system in non-small cell lung cancer: A systematic review and meta-analysis. Molecular and Clinical Oncology, 8(1), 127–132. https://doi.org/10.3892/MCO.2017.1484

  44. Lee, H. J., Choe, G., Jheon, S., Sung, S. W., Lee, C. T., & Chung, J. H. (2010). CD24, a novel cancer biomarker, predicting disease-free survival of non-small cell lung carcinomas: A retrospective study of prognostic factor analysis from the viewpoint of forthcoming (seventh) new TNM classification. Journal of Thoracic Oncology, 5(5), 649–657. https://doi.org/10.1097/JTO.0B013E3181D5E554

    Article  PubMed  Google Scholar 

  45. Robichaux, J. P., Le, X., Vijayan, R. S. K., Hicks, J. K., Heeke, S., Elamin, Y. Y., … Heymach, J. v. (2021). Structure-based classification predicts drug response in EGFR-mutant NSCLC. Nature, 597(7878), 732–737. https://doi.org/10.1038/s41586-021-03898-1

  46. Salgia, R., Pharaon, R., Mambetsariev, I., Nam, A., & Sattler, M. (2021). The improbable targeted therapy: KRAS as an emerging target in non-small cell lung cancer (NSCLC). Cell Reports Medicine, 2(1), 100186. https://doi.org/10.1016/J.XCRM.2020.100186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chang, G. C., Yang, T. Y., Chen, K. C., Hsu, K. H., Huang, Y. H., Su, K. Y., … Tseng, J. sen. (2020). ALK variants, PD-L1 expression, and their association with outcomes in ALK-positive NSCLC patients. Scientific Reports, 10(1), 1–9. https://doi.org/10.1038/s41598-020-78152-1

  48. Paik, P. K., Arcila, M. E., Fara, M., Sima, C. S., Miller, V. A., Kris, M. G., … Riely, G. J. (2011). Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. Journal of Clinical Oncology, 29(15), 2046. https://doi.org/10.1200/JCO.2010.33.1280

  49. Roskoski, R. (2017). ROS1 protein-tyrosine kinase inhibitors in the treatment of ROS1 fusion protein-driven non-small cell lung cancers. Pharmacological Research, 121, 202–212. https://doi.org/10.1016/J.PHRS.2017.04.022

    Article  CAS  PubMed  Google Scholar 

  50. Gendarme, S., Bylicki, O., Chouaid, C., & Guisier, F. (2022). ROS-1 fusions in non-small-cell lung cancer: Evidence to date. Current Oncology, 29(2), 641. https://doi.org/10.3390/CURRONCOL29020057

    Article  PubMed  PubMed Central  Google Scholar 

  51. Drilon, A., Lin, J. J., Filleron, T., Ni, A., Milia, J., Bergagnini, I., … Gautschi, O. (2018). Frequency of brain metastases and multikinase inhibitor outcomes in patients with RET–Rearranged lung cancers. Journal of Thoracic Oncology, 13(10), 1595–1601. https://doi.org/10.1016/J.JTHO.2018.07.004

  52. Ou, S.-H. I., Sokol, E. S., Trabucco, S. E., Jin, D. X., Frampton, G. M., Graziano, S. L., … Ross, J. S. (2019). NTRK1-3 genomic fusions in non-small cell lung cancer (NSCLC) determined by comprehensive genomic profiling. Annals of Oncology, 30, v638. https://doi.org/10.1093/ANNONC/MDZ260.071

  53. Saffroy, R., Fallet, V., Girard, N., Mazieres, J., Sibilot, D. M., Lantuejoul, S., … Wislez, M. (2017). MET exon 14 mutations as targets in routine molecular analysis of primary sarcomatoid carcinoma of the lung. Oncotarget, 8(26), 42428. https://doi.org/10.18632/ONCOTARGET.16403

  54. Bean, J., Brennan, C., Shih, J. Y., Riely, G., Viale, A., Wang, L., … Pao, W. (2007). MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proceedings of the National Academy of Sciences of the United States of America, 104(52), 20932–20937. https://doi.org/10.1073/PNAS.0710370104/SUPPL_FILE/10370FIG6.PDF

  55. Arcila, M. E., Chaft, J. E., Nafa, K., Roy-Chowdhuri, S., Lau, C., Zaidinski, M., … Ladanyi, M. (2012). Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clinical Cancer Research, 18(18), 4910–4918. https://doi.org/10.1158/1078-0432.CCR-12-0912/286497/AM/PREVALENCE-CLINICOPATHOLOGIC-ASSOCIATIONS-AND

  56. Pillai, R. N., Behera, M., Berry, L. D., Rossi, M. R., Kris, M. G., Johnson, B. E., … Khuri, F. R. (2017). HER2 mutations in lung adenocarcinomas: A report from the Lung Cancer Mutation Consortium. Cancer, 123(21), 4099–4105. https://doi.org/10.1002/CNCR.30869

  57. Stinchcombe, T. E., & Johnson, G. L. (2014). MEK inhibition in non-small cell lung cancer. Lung Cancer, 86(2), 121–125. https://doi.org/10.1016/J.LUNGCAN.2014.09.005

    Article  PubMed  Google Scholar 

  58. Lee, M. W., Kim, D. S., Lee, J. H., Lee, B. S., Lee, S. H., Jung, H. L., … Koo, H. H. (2011). Roles of AKT1 and AKT2 in non-small cell lung cancer cell survival, growth, and migration. Cancer Science, 102(10), 1822–1828. https://doi.org/10.1111/J.1349-7006.2011.02025.X

  59. Chorner, P. M., & Moorehead, R. A. (2018). A-674563, a putative AKT1 inhibitor that also suppresses CDK2 activity, inhibits human NSCLC cell growth more effectively than the pan-AKT inhibitor, MK-2206. PLOS ONE, 13(2), e0193344. https://doi.org/10.1371/JOURNAL.PONE.0193344

    Article  PubMed  PubMed Central  Google Scholar 

  60. Bie, F., Tian, H., Sun, N., Zang, R., Zhang, M., Song, P., … Gao, S. (2022). Research progress of anti-PD-1/PD-L1 immunotherapy related mechanisms and predictive biomarkers in NSCLC. Frontiers in Oncology, 12, 331. https://doi.org/10.3389/FONC.2022.769124/BIBTEX

  61. Rowshanravan, B., Halliday, N., & Sansom, D. M. (2018). CTLA-4: A moving target in immunotherapy. Blood, 131(1), 58–67. https://doi.org/10.1182/BLOOD-2017-06-741033

    Article  CAS  PubMed  Google Scholar 

  62. Wang, L., Liu, F., Li, J., Ma, L., Feng, H., Liu, Q., … Ji, J. (2021). From anti-pd-1/pd-l1 to ctla-4 and to muc1—Is the better response to treatment in smokers of cancer patients drug specific? Journal of Personalized Medicine, 11(9), 914. https://doi.org/10.3390/JPM11090914/S1

  63. Li, S. J., Huang, J., Zhou, X. D., Zhang, W. B., Lai, Y. T., & Che, G. W. (2016). Clinicopathological and prognostic significance of Oct-4 expression in patients with non-small cell lung cancer: A systematic review and meta-analysis. Journal of Thoracic Disease, 8(7), 1587. https://doi.org/10.21037/JTD.2016.06.01

    Article  PubMed  PubMed Central  Google Scholar 

  64. Chen, T.-Y., Zhou, J., Li, P.-C., Tang, C.-H., Xu, K., Li, T., & Ren, T. (2022). SOX2 knockdown with siRNA reverses cisplatin resistance in NSCLC by regulating APE1 signaling. Medical Oncology, 39(3), 1–10. https://doi.org/10.1007/S12032-021-01626-3/FIGURES/6

    Article  Google Scholar 

  65. Gao, W., Qi, C. Q., Feng, M. G., Yang, P., Liu, L., & Sun, S. H. (2020). SOX2-induced upregulation of lncRNA LINC01561 promotes non-small-cell lung carcinoma progression by sponging miR-760 to modulate SHCBP1 expression. Journal of Cellular Physiology, 235(10), 6684–6696. https://doi.org/10.1002/JCP.29564

    Article  CAS  PubMed  Google Scholar 

  66. Wang, Y., Zhou, P., Cui, C., He, X., Bian, Y., & Wang, X. (2021). The expression of Nanog protein and fibroblast growth factor-inducible molecule 14 in patients with non-small cell lung cancer and their relationship with pathological characteristics and prognosis. Translational Cancer Research, 10(5), 2470. https://doi.org/10.21037/TCR-21-724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Liu, L., Zhu, H., Liao, Y., Wu, W., Liu, L., Liu, L., … Lin, H. wen. (2020). Inhibition of Wnt/β-catenin pathway reverses multi-drug resistance and EMT in Oct4+/Nanog+ NSCLC cells. Biomedicine & Pharmacotherapy, 127, 110225. https://doi.org/10.1016/J.BIOPHA.2020.110225

  68. Seo, A. N., Yang, J. M., Kim, H., Jheon, S., Kim, K., Lee, C. T., … Paik, J. H. (2014). Clinicopathologic and prognostic significance of c-MYC copy number gain in lung adenocarcinomas. British Journal of Cancer, 110(11), 2688–2699. https://doi.org/10.1038/bjc.2014.218

  69. Flacco, A., Ludovini, V., Bianconi, F., Ragusa, M., Bellezza, G., Tofanetti, F. R., … Crinò, L. (2015). MYC and human telomerase gene (TERC) copy number gain in early-stage non-small cell lung cancer. American Journal of Clinical Oncology, 38(2), 152. https://doi.org/10.1097/COC.0000000000000012

  70. Tadokoro Akira, Kanaji Nobuhiro, Liu Dage, Yokomise Hiroyasu, Haba Reiji, Ishii Tomoya, … Bandho Shuji. (2016). Vimentin regulates invasiveness and is a poor prognostic marker in non-small cell lung cancer. Anticancer Research, 36, 1545–1552. Retrieved on November 24, 2022, from https://ar.iiarjournals.org/content/36/4/1545.short

  71. Zhang, X., Liu, G., Kang, Y., Dong, Z., Qian, Q., & Ma, X. (2013). N-cadherin expression is associated with acquisition of EMT phenotype and with enhanced invasion in erlotinib-resistant lung cancer cell lines. PLOS ONE, 8(3), e57692. https://doi.org/10.1371/JOURNAL.PONE.0057692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Qin, Q., Li, X., Liang, X., Zeng, L., Wang, J., Sun, L., & Zhong, D. (2021). Targeting the EMT transcription factor Snail overcomes resistance to osimertinib in EGFR-mutant non-small cell lung cancer. Thoracic Cancer, 12(11), 1708–1715. https://doi.org/10.1111/1759-7714.13906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Yochum, Z. A., Cades, J., Wang, H., Chatterjee, S., Simons, B. W., O’Brien, J. P., … Burns, T. F. (2018). Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer. Oncogene, 38(5), 656–670. https://doi.org/10.1038/s41388-018-0482-y

  74. Nurwidya, F., Takahashi, F., Winardi, W., Tajima, K., Mitsuishi, Y., Murakami, A., … Takahashi, K. (2021). Zinc-finger E-box-binding homeobox 1 (ZEB1) plays a crucial role in the maintenance of lung cancer stem cells resistant to gefitinib. Thoracic Cancer, 12(10), 1536–1548. https://doi.org/10.1111/1759-7714.13937

  75. Zhong, J., Guo, Z., Fan, L., Zhao, X., Zhao, B., Cao, Z., … Zhao, J. (2019). ABCB1 polymorphism predicts the toxicity and clinical outcome of lung cancer patients with taxane-based chemotherapy. Thoracic Cancer, 10(11), 2088–2095. https://doi.org/10.1111/1759-7714.13184

  76. Tang, L. N., Zhang, C. L., He, H. R., Pan, Z. Y., Fan, D., He, Y. L., … Li, Y. J. (2018). Associations between ABCG2 gene polymorphisms and gefitinib toxicity in non-small cell lung cancer: A meta-analysis. OncoTargets and Therapy, 11, 665. https://doi.org/10.2147/OTT.S154244

  77. Fan, C. C., Tsai, S. T., Lin, C. Y., Chang, L. C., Yang, J. C., Chen, G. Y., … Chang, W. C. (2020). EFHD2 contributes to non-small cell lung cancer cisplatin resistance by the activation of NOX4-ROS-ABCC1 axis. Redox Biology, 34, 101571. https://doi.org/10.1016/J.REDOX.2020.101571

  78. Rebollido-Rios, R., Venton, G., Sánchez-Redondo, S., Iglesias i Felip, C., Fournet, G., González, E., … Perez-Alea, M. (2020). Dual disruption of aldehyde dehydrogenases 1 and 3 promotes functional changes in the glutathione redox system and enhances chemosensitivity in nonsmall cell lung cancer. Oncogene, 39(13), 2756–2771. https://doi.org/10.1038/s41388-020-1184-9

  79. Shao, C., Sullivan, J. P., Girard, L., Augustyn, A., Yenerall, P., Rodriguez-Canales, J., … Minna, J. D. (2014). Essential role of aldehyde dehydrogenase 1A3 for the maintenance of non-small cell lung cancer stem cells is associated with the STAT3 pathway. Clinical Cancer Research, 20(15), 4154–4166. https://doi.org/10.1158/1078-0432.CCR-13-3292/176363/AM/ESSENTIAL-ROLE-OF-ALDEHYDE-DEHYDROGENASE-1A3

  80. Howington, J. A., Blum, M. G., Chang, A. C., Balekian, A. A., & Murthy, S. C. (2013). Treatment of stage I and II non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 143(5), e278S-e313S. https://doi.org/10.1378/CHEST.12-2359

    Article  CAS  PubMed  Google Scholar 

  81. Detterbeck, F. C., Lewis, S. Z., Diekemper, R., Addrizzo-Harris, D., & Alberts, W. M. (2013). Executive summary: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest, 143(5), 7S-37S. https://doi.org/10.1378/chest.12-2377

    Article  CAS  PubMed  Google Scholar 

  82. Cattaneo, S. M., Park, B. J., Wilton, A. S., Seshan, V. E., Bains, M. S., Downey, R. J., … Rusch, V. W. (2008). Use of video-assisted thoracic surgery for lobectomy in the elderly results in fewer complications. The Annals of Thoracic Surgery, 85(1), 231–236. https://doi.org/10.1016/J.ATHORACSUR.2007.07.080

  83. Aisner, D. L., Akerley, W., Bauman, J. R., Bruno, D. S., Chang, J. Y., Chirieac, L. R., … Miranda Hughes, O. (2022). NCCN Guidelines Version 5.2022 non-small cell lung cancer continue NCCN guidelines panel disclosures. Retrieved from https://www.nccn.org/home/member-

  84. Lewis, J., Gillaspie, E. A., Osmundson, E. C., & Horn, L. (2018). Before or after: Evolving neoadjuvant approaches to locally advanced non-small cell lung cancer. Frontiers in Oncology, 8(JAN), 5. https://doi.org/10.3389/FONC.2018.00005/BIBTEX

    Article  PubMed  PubMed Central  Google Scholar 

  85. Bunn, P. A. Jr., Schenk, E., Pacheco, J., & Dimou, A. (2019). New developments in neoadjuvant therapy for lung cancer. Oncology, 33(3), 101–109. Retrieved on November 27, 2022, from https://web.p.ebscohost.com/abstract?direct=true&profile=ehost&scope=site&authtype=crawler&jrnl=08909091&AN=135377400&h=IQR9i3xnyJCczLGksnYFPy5Q5dNjQN26poyli8p4kQKbu%2f%2fSWIRJIyKLVngpzAQiyW86twSh3B52HRs5ZhcnRg%3d%3d&crl=c&resultNs=AdminWebAuth&resultLocal=ErrCrlNotAuth&crlhashurl=login.aspx%3fdirect%3dtrue%26profile%3dehost%26scope%3dsite%26authtype%3dcrawler%26jrnl%3d08909091%26AN%3d135377400

  86. NSCLC Meta-analyses Collaborative Group. (2010). Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: Two meta-analyses of individual patient data. The Lancet, 375(9722), 1267–1277. https://doi.org/10.1016/S0140-6736(10)60059-1

    Article  CAS  Google Scholar 

  87. Voelker, R. (2021). Adjuvant therapy approved for NSCLC. JAMA, 325(5), 426–426. https://doi.org/10.1001/JAMA.2021.0168

    Article  PubMed  Google Scholar 

  88. Drugs Approved for Lung Cancer - NCI. (2021). National Institute of Health (NIH). Retrieved September 21, 2021, from https://www.cancer.gov/about-cancer/treatment/drugs/lung

  89. Smith, C., Perfetti, T., & King, J. (2008). Perspectives on pulmonary inflammation and lung cancer risk in cigarette smokers. Inhalation Toxicology, 18(9), 667–677. https://doi.org/10.1080/08958370600742821

    Article  CAS  Google Scholar 

  90. Sun, S. C., Chang, J. H., & Jin, J. (2013). Regulation of nuclear factor-κB in autoimmunity. Trends in Immunology, 34(6), 282–289. https://doi.org/10.1016/J.IT.2013.01.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Yang, L., Zhou, Y., Li, Y., Zhou, J., Wu, Y., Cui, Y., … Hong, Y. (2015). Mutations of p53 and KRAS activate NF-κB to promote chemoresistance and tumorigenesis via dysregulation of cell cycle and suppression of apoptosis in lung cancer cells. Cancer Letters, 357(2), 520–526. https://doi.org/10.1016/J.CANLET.2014.12.003

  92. Jones, D. R., Broad, R. M., Madrid, L. V., Baldwin, A. S., & Mayo, M. W. (2000). Inhibition of NF-κB sensitizes non–small cell lung cancer cells to chemotherapy-induced apoptosis. The Annals of Thoracic Surgery, 70(3), 930–936. https://doi.org/10.1016/S0003-4975(00)01635-0

    Article  CAS  PubMed  Google Scholar 

  93. Li, M., Liu, P., Wang, B., Zhou, J., & Yang, J. (2022). Inhibition of nuclear factor kappa B as a therapeutic target for lung cancer. Alternative Therapies in Health and Medicine, 28(1), 44–51.

    PubMed  Google Scholar 

  94. Khalaf, M. M., Abo-Youssef, A. M., Malak, M. N., & Hamzawy, M. A. (2022). Novel therapeutic modalities target cell signaling of renin-angiotensin system/NF-κB-induced cell cycle arrest and apoptosis in urethane-induced lung cancer in mice: An in vivo study. Journal of Biochemical and Molecular Toxicology, 36(10), e23162. https://doi.org/10.1002/JBT.23162

    Article  CAS  PubMed  Google Scholar 

  95. Li, E., Xu, Z., Zhao, H., Sun, Z., Wang, L., Guo, Z., … Wang, Q. (2015). Macrophages promote benzopyrene-induced tumor transformation of human bronchial epithelial cells by activation of NF-κB and STAT3 signaling in a bionic airway chip culture and in animal models. Oncotarget, 6(11), 8900. https://doi.org/10.18632/ONCOTARGET.3561

  96. Rasmi, R. R., Sakthivel, K. M., & Guruvayoorappan, C. (2020). NF-κB inhibitors in treatment and prevention of lung cancer. Biomedicine & Pharmacotherapy, 130, 110569. https://doi.org/10.1016/J.BIOPHA.2020.110569

    Article  CAS  Google Scholar 

  97. Kim, M., Vu, N. T., Wang, X., Bulut, G. B., Wang, M.-H., Uram-Tuculescu, C., … Chalfant, C. E. (2022). Caspase 9b drives cellular transformation, lung inflammation, and lung tumorigenesis. Molecular Cancer Research: MCR, 20(8), 1284. https://doi.org/10.1158/1541-7786.MCR-21-0905

  98. Zhang, X. L., Dang, Y. W., Li, P., Rong, M. H., Hou, X. X., Luo, D. Z., & Chen, G. (2015). Expression of tumor necrosis factor receptor-associated factor 6 in lung cancer tissues. Asian Pacific Journal of Cancer Prevention, 15(24), 10591–10596.

    Article  Google Scholar 

  99. Ryan, S. L., Beard, S., Barr, M. P., Umezawa, K., Heavey, S., Godwin, P., … Baird, A. M. (2019). Targeting NF-κB-mediated inflammatory pathways in cisplatin-resistant NSCLC. Lung Cancer, 135, 217–227. https://doi.org/10.1016/J.LUNGCAN.2019.07.006

  100. Jiang, N., Dong, X. P., Zhang, S. L., You, Q. Y., Jiang, X. T., & Zhao, X. G. (2016). Triptolide reverses the taxol resistance of lung adenocarcinoma by inhibiting the NF-κB signaling pathway and the expression of NF-κB-regulated drug-resistant genes. Molecular Medicine Reports, 13(1), 153–159. https://doi.org/10.3892/MMR.2015.4493/HTML

    Article  CAS  PubMed  Google Scholar 

  101. Denlinger, C. E., Rundall, B. K., Keller, M. D., & Jones, D. R. (2004). Proteasome inhibition sensitizes non-small-cell lung cancer to gemcitabine-induced apoptosis. The Annals of Thoracic Surgery, 78(4), 1207–1214. https://doi.org/10.1016/J.ATHORACSUR.2004.04.029

    Article  PubMed  Google Scholar 

  102. Gu, L., Wang, Z., Zuo, J., Li, H., & Zha, L. (2018). Prognostic significance of NF-κB expression in non-small cell lung cancer: A meta-analysis. PLOS ONE, 13(5), e0198223. https://doi.org/10.1371/JOURNAL.PONE.0198223

    Article  PubMed  PubMed Central  Google Scholar 

  103. Iosef, C., Alastalo, T. P., Hou, Y., Chen, C., Adams, E. S., Lyu, S. C., … Alvira, C. M. (2012). Inhibiting NF-κB in the developing lung disrupts angiogenesis and alveolarization. American Journal of Physiology - Lung Cellular and Molecular Physiology, 302(10). https://doi.org/10.1152/AJPLUNG.00230.2011/ASSET/IMAGES/LARGE/ZH50091261040006.JPEG

  104. Pikarsky, E., & Ben-Neriah, Y. (2006). NF-κB inhibition: A double-edged sword in cancer? European Journal of Cancer, 42(6), 779–784. https://doi.org/10.1016/J.EJCA.2006.01.011

    Article  CAS  PubMed  Google Scholar 

  105. Xiao, Z., Jiang, Q., Willette-Brown, J., Xi, S., Zhu, F., Burkett, S., … Hu, Y. (2013). The pivotal role of IKKα in the development of spontaneous lung squamous cell carcinomas. Cancer Cell, 23(4), 527–540. https://doi.org/10.1016/J.CCR.2013.03.009

  106. Xia, Y., Yeddula, N., Leblanc, M., Ke, E., Zhang, Y., Oldfield, E., … Verma, I. M. (2012). Reduced cell proliferation by IKK2 depletion in a mouse lung-cancer model. Nature Cell Biology, 14(3), 257–265. https://doi.org/10.1038/ncb2428

  107. Kimura, Y. N., Watari, K., Fotovati, A., Hosoi, F., Yasumoto, K., Izumi, H., … Ono, M. (2007). Inflammatory stimuli from macrophages and cancer cells synergistically promote tumor growth and angiogenesis. Cancer Science, 98(12), 2009–2018. https://doi.org/10.1111/J.1349-7006.2007.00633.X

  108. Song, H., Ye, X., Liao, Y., Zhang, S., Xu, D., Zhong, S., … Deng, J. (2023). NF-κB represses retinoic acid receptor–mediated GPRC5A transactivation in lung epithelial cells to promote neoplasia. JCI Insight, 8(1). https://doi.org/10.1172/JCI.INSIGHT.153976

  109. Shien, K., Toyooka, S., Yamamoto, H., Soh, J., Jida, M., Thu, K. L., … Miyosh, S. (2013). Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells. Cancer Research, 73(10), 3051–3061. https://doi.org/10.1158/0008-5472.CAN-12-4136/650925/AM/ACQUIRED-RESISTANCE-TO-EGFR-INHIBITORS-IS

  110. Sparreboom, A., Danesi, R., Ando, Y., Chan, J., & Figg, W. D. (2003). Pharmacogenomics of ABC transporters and its role in cancer chemotherapy. Drug Resistance Updates, 6(2), 71–84. https://doi.org/10.1016/S1368-7646(03)00005-0

    Article  CAS  PubMed  Google Scholar 

  111. Wang, Y., Lei, L., Zheng, Y. W., Zhang, L., Li, Z. H., Shen, H. Y., … Xu, H. T. (2018). Odd-skipped related 1 inhibits lung cancer proliferation and invasion by reducing Wnt signaling through the suppression of SOX9 and β-catenin. Cancer Science, 109(6), 1799–1810. https://doi.org/10.1111/CAS.13614

  112. Hu, Y., Zang, J., Qin, X., Yan, D., Cao, H., Zhou, L., … Feng, J. F. (2017). Epithelial-to-mesenchymal transition correlates with gefitinib resistance in NSCLC cells and the liver X receptor ligand GW3965 reverses gefitinib resistance through inhibition of vimentin. OncoTargets and Therapy, 10, 2341. https://doi.org/10.2147/OTT.S124757

  113. Jiang, L., Huang, J., Hu, Y., Lu, P., Luo, Q., & Wang, L. (2020). Gli promotes tumor progression through regulating epithelial-mesenchymal transition in non-small-cell lung cancer. Journal of Cardiothoracic Surgery, 15(1), 1–8. https://doi.org/10.1186/S13019-020-1049-X/FIGURES/5

    Article  Google Scholar 

  114. Leprieur, E. G., Tolani, B., Li, H., Leguay, F., Hoang, N. T., Acevedo, L. A., … He, B. (2017). Membrane-bound full-length Sonic Hedgehog identifies cancer stem cells in human non-small cell lung cancer. Oncotarget, 8(61), 103744. https://doi.org/10.18632/ONCOTARGET.21781

  115. Colaluca, I. N., Tosoni, D., Nuciforo, P., Senic-Matuglia, F., Galimberti, V., Viale, G., … di Fiore, P. P. (2008). NUMB controls p53 tumour suppressor activity. Nature, 451(7174), 76–80. https://doi.org/10.1038/nature06412

  116. Ma, Y., Li, M., Si, J., Xiong, Y., Lu, F., Zhang, J., … Yang, Y. (2016). Blockade of Notch3 inhibits the stem-like property and is associated with ALDH1A1 and CD44 via autophagy in non-small lung cancer. International Journal of Oncology, 48(6), 2349–2358. https://doi.org/10.3892/IJO.2016.3464/HTML

  117. Chen, B., Shen, Z., Wu, D., Xie, X., Xu, X., Lv, L., … Gan, X. (2019). Glutathione peroxidase 1 promotes NSCLC resistance to cisplatin via ROS-induced activation of PI3K/AKT pathway. BioMed Research International, 2019. https://doi.org/10.1155/2019/7640547

  118. Zhang, Y., Han, C. Y., Duan, F. G., Fan, X. X., Yao, X. J., Parks, R. J., … Leung, E. L. H. (2019). P53 sensitizes chemoresistant non-small cell lung cancer via elevation of reactive oxygen species and suppression of EGFR/PI3K/AKT signaling. Cancer Cell International, 19(1), 1–13. https://doi.org/10.1186/S12935-019-0910-2/FIGURES/6

  119. Dean, E. J., Ward, T., Pinilla, C., Houghten, R., Welsh, K., Makin, G., … Dive, C. (2009). A small molecule inhibitor of XIAP induces apoptosis and synergises with vinorelbine and cisplatin in NSCLC. British Journal of Cancer, 102(1), 97–103. https://doi.org/10.1038/sj.bjc.6605418

  120. Ye, L., Pu, C., Tang, J., Wang, Y., Wang, C., Qiu, Z., … Peng, W. (2019). Transmembrane-4 L-six family member-1 (TM4SF1) promotes non-small cell lung cancer proliferation, invasion and chemo-resistance through regulating the DDR1/Akt/ERK-mTOR axis. Respiratory Research, 20(1), 1–10. https://doi.org/10.1186/S12931-019-1071-5/FIGURES/4

  121. Jiang, P., Xu, H., Xu, C., Chen, A., Chen, L., Zhou, M., … Feng, Q. (2018). NEAT1 contributes to the CSC-like traits of A549/CDDP cells via activating Wnt signaling pathway. Chemico-Biological Interactions, 296, 154–161. https://doi.org/10.1016/J.CBI.2018.10.001

  122. Najafzadeh, B., Motafakkerazad, R., Najafi, S., Amini, M., Alemohammad, H., Vasefifar, P., & Baradaran, B. (2022). Nanog suppression enhanced the chemosensitivity of human non-small-cell lung cancer cells to cisplatin and inhibited cell migration. Pathology - Research and Practice, 233, 153869. https://doi.org/10.1016/J.PRP.2022.153869

    Article  CAS  PubMed  Google Scholar 

  123. Baghbani, E., Noorolyai, S., Rahmani, S., Shanehbandi, D., Shadbad, M. A., Aghebati-Maleki, L., … Baradaran, B. (2022). Silencing tumor-intrinsic CD73 enhances the chemosensitivity of NSCLC and potentiates the anti-tumoral effects of cisplatin: An in vitro study. Biomedicine & Pharmacotherapy, 145, 112370. https://doi.org/10.1016/J.BIOPHA.2021.112370

  124. Wang, Q., Geng, F., Zhou, H., Chen, Y., Du, J., Zhang, X., … Zhao, H. (2019). MDIG promotes cisplatin resistance of lung adenocarcinoma by regulating ABC transporter expression via activation of the WNT/β-catenin signaling pathway. Oncology Letters, 18(4), 4294–4307. https://doi.org/10.3892/OL.2019.10774/HTML

  125. Huang, W. C., Kuo, K. T., Wang, C. H., Yeh, C. T., & Wang, Y. (2019). Cisplatin resistant lung cancer cells promoted M2 polarization of tumor-associated macrophages via the Src/CD155/MIF functional pathway. Journal of Experimental and Clinical Cancer Research, 38(1), 1–17. https://doi.org/10.1186/S13046-019-1166-3/FIGURES/8

    Article  Google Scholar 

  126. Larionova, I., Cherdyntseva, N., Liu, T., Patysheva, M., Rakina, M., & Kzhyshkowska, J. (2019). Interaction of tumor-associated macrophages and cancer chemotherapy. Oncoimmunology, 8(7). https://doi.org/10.1080/2162402X.2019.1596004

  127. Li, L., Chen, C., Xiang, Q., Fan, S., Xiao, T., Chen, Y., & Zheng, D. (2022). Transient receptor potential cation channel subfamily V member 1 expression promotes chemoresistance in non-small-cell lung cancer. Frontiers in Oncology, 12, 1167. https://doi.org/10.3389/FONC.2022.773654/BIBTEX

    Article  CAS  Google Scholar 

  128. Yu, W. K., Wang, Z., Fong, C. C., Liu, D., Yip, T. C., Au, S. K., … Yang, M. (2017). Chemoresistant lung cancer stem cells display high DNA repair capability to remove cisplatin-induced DNA damage. British Journal of Pharmacology, 174(4), 302–313. https://doi.org/10.1111/BPH.13690

  129. Suzuki, T., Sirimangkalakitti, N., Baba, A., Toyoshima-Nagasaki, R., Enomoto, Y., Saito, N., & Ogasawara, Y. (2022). Characterization of the nucleotide excision repair pathway and evaluation of compounds for overcoming the cisplatin resistance of non-small cell lung cancer cell lines. Oncology Reports, 47(4), 1–9. https://doi.org/10.3892/OR.2022.8281/HTML

    Article  CAS  Google Scholar 

  130. Wang, R., Li, A., Liu, J., Fang, M., Zhu, Y., Huang, J., … You, Q. (2022). BEZ235 reduction of cisplatin resistance on wild-type EGFR non-small cell lung cancer cells. https://doi.org/10.1080/1120009X.2022.2045826

  131. Long, K., Gu, L., Li, L., Zhang, Z., Li, E., Zhang, Y., … Hu, Z. (2021). Small-molecule inhibition of APE1 induces apoptosis, pyroptosis, and necroptosis in non-small cell lung cancer. Cell Death & Disease, 12(6), 1–15. https://doi.org/10.1038/s41419-021-03804-7

  132. Chen, P., Li, J., Chen, Y. C., Qian, H., Chen, Y. J., Su, J. Y., … Lan, T. (2016). The functional status of DNA repair pathways determines the sensitization effect to cisplatin in non-small cell lung cancer cells. Cellular Oncology, 39(6), 511–522. https://doi.org/10.1007/S13402-016-0291-7/FIGURES/8

  133. Fan, X. Z., Chen, Y. F., Zhang, S. B., He, D. H., Wei, S. F., Wang, Q., … Liu, Y. Q. (2021). Centipeda minima extract sensitizes lung cancer cells to DNA-crosslinking agents via targeting Fanconi anemia pathway. Phytomedicine, 91, 153689. https://doi.org/10.1016/J.PHYMED.2021.153689

  134. Xue, P., Zhang, G., Zhang, H., Cui, S., Zhang, L., Yu, T., … Lu, X. (2022). A miR-15a related polymorphism affects NSCLC prognosis via altering ERCC1 repair to platinum-based chemotherapy. Journal of Cellular and Molecular Medicine, 26(21), 5439–5451. https://doi.org/10.1111/JCMM.17566

  135. Ceppi, P., Novello, S., Cambieri, A., Longo, M., Monica, V., lo Iacono, M., … Scagliotti, G. (2009). Polymerase η mRNA expression predicts survival of non-small cell lung cancer patients treated with platinum-based chemotherapy. Clinical Cancer Research, 15(3), 1039–1045. https://doi.org/10.1158/1078-0432.CCR-08-1227

  136. Doles, J., Oliver, T. G., Cameron, E. R., Hsu, G., Jacks, T., Walker, G. C., & Hemann, M. T. (2010). Suppression of Rev3, the catalytic subunit of Pol?, sensitizes drug-resistant lung tumors to chemotherapy. Proceedings of the National Academy of Sciences of the United States of America, 107(48), 20786–20791. https://doi.org/10.1073/PNAS.1011409107/SUPPL_FILE/PNAS.201011409SI.PDF

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Li, Q., Yang, Z., Chen, M., & Liu, Y. (2016). Downregulation of microRNA-196a enhances the sensitivity of non-small cell lung cancer cells to cisplatin treatment. International Journal of Molecular Medicine, 37(4), 1067–1074. https://doi.org/10.3892/IJMM.2016.2513/HTML

    Article  PubMed  Google Scholar 

  138. Zhou, D. H., Wang, X., & Feng, Q. (2014). EGCG enhances the efficacy of cisplatin by downregulating hsa-miR-98-5p in NSCLC A549 cells. Nutrition and Cancer, 66(4), 636–644. https://doi.org/10.1080/01635581.2014.894101

    Article  CAS  PubMed  Google Scholar 

  139. Wang, H., Zhu, L. J., Yang, Y. C., Wang, Z. X., & Wang, R. (2014). MiR-224 promotes the chemoresistance of human lung adenocarcinoma cells to cisplatin via regulating G1/S transition and apoptosis by targeting p21WAF1/CIP1. British Journal of Cancer, 111(2), 339–354. https://doi.org/10.1038/bjc.2014.157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Liu, K., Tian, H., Zhang, Y., Zao, H., & Ma, K. (2018). miR-451 selectively increases sensitivity to cisplatin in ERCC1-high non-small cell lung cancer cells. Journal of Cellular Biochemistry, 120(7), 12074. https://doi.org/10.1002/JCB.26657

    Article  Google Scholar 

  141. Chen, M. J., Wu, D. W., Wang, G. C., Wang, Y. C., Chen, C. Y., & Lee, H. (2018). MicroRNA-630 may confer favorable cisplatin-based chemotherapy and clinical outcomes in non-small cell lung cancer by targeting Bcl-2. Oncotarget, 9(17), 13758. https://doi.org/10.18632/ONCOTARGET.24474

    Article  PubMed  PubMed Central  Google Scholar 

  142. Zhang, L., Cai, J., Fang, L., Huang, Y., Li, R., Xu, X., … Li, M. (2017). Simultaneous overactivation of Wnt/β-catenin and TGFβ signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC. Nature Communications, 8(1), 1–19. https://doi.org/10.1038/ncomms15870

  143. Chen, W., Zhao, W., Zhang, L., Wang, L., Wang, J., Wan, Z., … Yu, L. (2017). MALAT1-miR-101-SOX9 feedback loop modulates the chemo-resistance of lung cancer cell to DDP via Wnt signaling pathway. Oncotarget, 8(55), 94317. https://doi.org/10.18632/ONCOTARGET.21693

  144. Xia, Y., He, Z., Liu, B., Wang, P., & Chen, Y. (2015). Downregulation of Meg3 enhances cisplatin resistance of lung cancer cells through activation of the WNT/β-catenin signaling pathway. Molecular Medicine Reports, 12(3), 4530–4537. https://doi.org/10.3892/MMR.2015.3897/HTML

    Article  CAS  PubMed  Google Scholar 

  145. Fu, X., Li, H., Liu, C., Hu, B., Li, T., & Wang, Y. (2016). Long noncoding RNA AK126698 inhibits proliferation and migration of non-small cell lung cancer cells by targeting Frizzled-8 and suppressing Wnt/β-catenin signaling pathway. OncoTargets and Therapy, 9, 3815. https://doi.org/10.2147/OTT.S100633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Liu, X., Huang, Z., Qian, W., Zhang, Q., & Sun, J. (2019). Silence of lncRNA UCA1 rescues drug resistance of cisplatin to non–small-cell lung cancer cells. Journal of Cellular Biochemistry, 120(6), 9243–9249. https://doi.org/10.1002/JCB.28200

    Article  CAS  PubMed  Google Scholar 

  147. Xu, C., Jiang, S., Ma, X., Jiang, Z., Pan, Y., Li, X., … Li, D. (2023). CRISPR-based DNA methylation editing of NNT rescues the cisplatin resistance of lung cancer cells by reducing autophagy. Archives of Toxicology, 97(2), 441–456. https://doi.org/10.1007/S00204-022-03404-0/FIGURES/7

  148. Gong, S., Wang, S., & Shao, M. (2022). Mechanism of METTL14-mediated m6A modification in non-small cell lung cancer cell resistance to cisplatin. Journal of Molecular Medicine, 100(12), 1771–1785. https://doi.org/10.1007/S00109-022-02268-2/FIGURES/8

    Article  CAS  PubMed  Google Scholar 

  149. Hou, H., Yu, X., Cong, P., Zhou, Y., Xu, Y., & Jiang, Y. (2019). Six2 promotes non-small cell lung cancer cell stemness via transcriptionally and epigenetically regulating E-cadherin. Cell Proliferation, 52(4), e12617. https://doi.org/10.1111/CPR.12617

    Article  PubMed  PubMed Central  Google Scholar 

  150. Liu, C., Chen, Z., Ding, X., Qiao, Y., & Li, B. (2022). Ubiquitin-specific protease 35 (USP35) mediates cisplatin-induced apoptosis by stabilizing BIRC3 in non-small cell lung cancer. Laboratory Investigation, 102(5), 524–533. https://doi.org/10.1038/s41374-021-00725-z

    Article  CAS  PubMed  Google Scholar 

  151. Yang, Y., Li, M., Zhou, X., Wang, W., Shao, Y., Yao, J., & Wang, X. (2022). PHF5A contributes to the maintenance of the cancer stem-like phenotype in non-small cell lung cancer by regulating histone deacetylase 8. Annals of Clinical & Laboratory Science, 52(3), 439–451.

    CAS  Google Scholar 

  152. Duan, L., Perez, R. E., Calhoun, S., & Maki, C. G. (2022). Inhibitors of Jumonji C domain-containing histone lysine demethylases overcome cisplatin and paclitaxel resistance in non-small cell lung cancer through APC/Cdh1-dependent degradation of CtIP and PAF15. Cancer Biology and Therapy, 23(1), 65–75. https://doi.org/10.1080/15384047.2021.2020060/SUPPL_FILE/KCBT_A_2020060_SM5347.ZIP

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Wang, Z., Ma, L. J., Kang, Y., Li, X., & Zhang, X. J. (2015). Dickkopf-3 (Dkk3) induces apoptosis in cisplatin-resistant lung adenocarcinoma cells via the Wnt/β-catenin pathway. Oncology Reports, 33(3), 1097–1106. https://doi.org/10.3892/OR.2014.3704/HTML

    Article  CAS  PubMed  Google Scholar 

  154. Tsuji, T., Nozaki, I., Miyazaki, M., Sakaguchi, M., Pu, H., Hamazaki, Y., … Namba, M. (2001). Antiproliferative activity of REIC/Dkk-3 and its significant down-regulation in non-small-cell lung carcinomas. Biochemical and Biophysical Research Communications, 289(1), 257–263. https://doi.org/10.1006/BBRC.2001.5972

  155. Li, Z., Qing, Y., Guan, W., Li, M., Peng, Y., Zhang, S., … Wang, D. (2014). Predictive value of APE1, BRCA1, ERCC1 and TUBB3 expression in patients with advanced non-small cell lung cancer (NSCLC) receiving first-line platinum-paclitaxel chemotherapy. Cancer Chemotherapy and Pharmacology, 74(4), 777–786. https://doi.org/10.1007/S00280-014-2562-1/TABLES/3

  156. Niu, X., Wu, T., Yin, Q., Gu, X., Li, G., Zhou, C., … Cui, H. (2022). Combination of paclitaxel and PXR antagonist SPA70 reverses paclitaxel-resistant non-small cell lung cancer. Cells, 11(19), 3094. https://doi.org/10.3390/CELLS11193094/S1

  157. Lin, H., Hu, B., He, X., Mao, J., Wang, Y., Wang, J., … Zhang, F. (2020). Overcoming taxol-resistance in A549 cells: A comprehensive strategy of targeting P-gp transporter, AKT/ERK pathways, and cytochrome P450 enzyme CYP1B1 by 4-hydroxyemodin. Biochemical Pharmacology, 171, 113733. https://doi.org/10.1016/J.BCP.2019.113733

  158. Weinberg, O. K., Marquez-Garban, D. C., Fishbein, M. C., Goodglick, L., Garban, H. J., Dubinett, S. M., & Pietras, R. J. (2005). Aromatase inhibitors in human lung cancer therapy. Cancer Research, 65(24), 11287–11291. https://doi.org/10.1158/0008-5472.CAN-05-2737

    Article  CAS  PubMed  Google Scholar 

  159. Huang, Y., Wang, X., Hu, R., Pan, G., & Lin, X. (2022). SOX2 regulates paclitaxel resistance of A549 non-small cell lung cancer cells via promoting transcription of ClC-3. Oncology Reports, 48(4), 1–12. https://doi.org/10.3892/OR.2022.8396/HTML

    Article  Google Scholar 

  160. Jiang, S., Luo, Y., Zhan, Z., Tang, Z., Zou, J., Ying, Y., … Luo, L. (2022). AMP-activated protein kinase re-sensitizes A549 to paclitaxel via up-regulating solute carrier organic anion transporter family member 1B3 expression. Cellular Signalling, 91, 110215. https://doi.org/10.1016/J.CELLSIG.2021.110215

  161. Min, H. Y., Lee, H. J., Suh, Y. A., Pei, H., Kwon, H., Jang, H. J., … Lee, H. Y. (2022). Targeting epidermal growth factor receptor in paclitaxel-resistant human breast and lung cancer cells with upregulated glucose-6-phosphate dehydrogenase. British Journal of Cancer, 127(4), 661–674. https://doi.org/10.1038/s41416-022-01843-1

  162. Nan, G., Zhao, S. H., Wang, T., Chao, D., Tian, R. F., Wang, W. J., … Cui, H. Y. (2022). CD147 supports paclitaxel resistance via interacting with RanBP1. Oncogene, 41(7), 983–996. https://doi.org/10.1038/s41388-021-02143-3

  163. Wang, W., Wang, J., Liu, S., Ren, Y., Wang, J., Liu, S., … Wang, L. (2022). An EHMT2/NFYA-ALDH2 signaling axis modulates the RAF pathway to regulate paclitaxel resistance in lung cancer. Molecular Cancer, 21(1), 1–18. https://doi.org/10.1186/S12943-022-01579-9/FIGURES/8

  164. Ren, J., Wang, D., Huang, H., Li, X., Zhuang, X., & Li, J. (2020). miR-1260b activates Wnt signaling by targeting secreted frizzled-related protein 1 to regulate taxane resistance in lung adenocarcinoma. Frontiers in Oncology, 10, 2186. https://doi.org/10.3389/FONC.2020.557327/BIBTEX

    Article  Google Scholar 

  165. Huang, J., Chen, Y., Li, J., Zhang, K., Chen, J., Chen, D., … Chen, L. (2016). Notch-1 confers chemoresistance in lung adenocarcinoma to taxanes through AP-1/microRNA-451 mediated regulation of MDR-1. Molecular Therapy - Nucleic Acids, 5, e375. https://doi.org/10.1038/MTNA.2016.82

  166. Li, X., Yang, B., Ren, H., Xiao, T., Zhang, L., Li, L., … Zhang, W. (2019). Hsa_circ_0002483 inhibited the progression and enhanced the taxol sensitivity of non-small cell lung cancer by targeting miR-182-5p. Cell Death & Disease, 10(12), 1–12. https://doi.org/10.1038/s41419-019-2180-2

  167. Guo, C., Wang, H., Jiang, H., Qiao, L., & Wang, X. (2022). Circ_0011292 enhances paclitaxel resistance in non-small cell lung cancer by regulating miR-379-5p/TRIM65 axis. Cancer Biotherapy and Radiopharmaceuticals, 37(2), 84–95. https://doi.org/10.1089/CBR.2019.3546https://home.liebertpub.com/cbr.

    Article  CAS  PubMed  Google Scholar 

  168. Jin, M., Zhang, F., Li, Q., Xu, R., Liu, Y., & Zhang, Y. (2022). Circ_0011292 knockdown mitigates progression and drug resistance in PTX-resistant non-small-cell lung cancer cells by regulating miR-433-3p/CHEK1 axis. Thoracic Cancer, 13(9), 1276–1288. https://doi.org/10.1111/1759-7714.14378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Cui, X., Zhang, B., Li, B., & Li, X. (2022). Circular RNA circ_0002360 regulates the taxol resistance and malignant behaviors of taxol-resistant non-small cell lung cancer cells by microRNA-585-3p-dependent modulation of G protein regulated inducer of neurite outgrowth 1. Bioengineered, 13(4), 9070–9085. https://doi.org/10.1080/21655979.2022.2053803/SUPPL_FILE/KBIE_A_2053803_SM7936.DOCX

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Wu, Y., Xie, J., Wang, H., Hou, S., & Feng, J. (2022). Circular RNA hsa_circ_0011298 enhances taxol resistance of non-small cell lung cancer by regulating miR-486-3p/CRABP2 axis. Journal of Clinical Laboratory Analysis, 36(5), e24408. https://doi.org/10.1002/JCLA.24408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Li, Y., Ma, Z., Luo, M., & Liang, R. (2022). Blocking circ_0010235 suppresses acquired paclitaxel resistance of non-small cell lung cancer by sponging miR-512-5p to modulate FAM83F expression. Anti-Cancer Drugs, 33(10), 1024–1034. https://doi.org/10.1097/CAD.0000000000001388

    Article  CAS  PubMed  Google Scholar 

  172. Xuan, X., Wang, Z., & Wang, Y. (2023). Circ_0058608 contributes to the progression and taxol resistance of non-small cell lung cancer by sponging miR-1299 to upregulate GBP1. Anti-Cancer Drugs, 34(1), 103–114. https://doi.org/10.1097/CAD.0000000000001346

    Article  CAS  PubMed  Google Scholar 

  173. Du, L., Guo, D., Sun, C., Yan, X., Lin, S., & Xu, S. (2023). CircPIM3 regulates taxol resistance in non-small cell lung cancer via miR-338-3p/TNFAIP8 axis. Anti-Cancer Drugs, 34(1), 115–125. https://doi.org/10.1097/CAD.0000000000001347

    Article  CAS  PubMed  Google Scholar 

  174. Wang, L., Zhang, Z., & Tian, H. (2023). Hsa_circ_0092887 targeting miR-490-5p/UBE2T promotes paclitaxel resistance in non-small cell lung cancer. Journal of Clinical Laboratory Analysis, 37(1), e24781. https://doi.org/10.1002/JCLA.24781

    Article  CAS  PubMed  Google Scholar 

  175. de Lucio, B., Manuel, V., & Barrera-Rodríguez, R. (2005). Characterization of human NSCLC cell line with innate etoposide-resistance mediated by cytoplasmic localization of topoisomerase II alpha. Cancer Science, 96(11), 774–783. https://doi.org/10.1111/J.1349-7006.2005.00111.X

    Article  PubMed  Google Scholar 

  176. Meylan, E., Dooley, A. L., Feldser, D. M., Shen, L., Turk, E., Ouyang, C., & Jacks, T. (2009). Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma. Nature, 462(7269), 104–107. https://doi.org/10.1038/nature08462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Kaewpiboon, C., Srisuttee, R., Malilas, W., Moon, J., Oh, S., Gwang Jeong, H., … Chung, Y. H. (2015). Upregulation of Stat1-HDAC4 confers resistance to etoposide through enhanced multidrug resistance 1 expression in human A549 lung cancer cells. Molecular Medicine Reports, 11(3), 2315–2321. https://doi.org/10.3892/MMR.2014.2949/HTML

  178. Siswanto, F. M., Tamura, A., Sakuma, R., & Imaoka, S. (2022). Yeast β-glucan increases etoposide sensitivity in lung cancer cell line A549 by suppressing nuclear factor erythroid 2-related factor 2 via the noncanonical nuclear factor kappa B pathway. Molecular Pharmacology, 101(4), 257–273. https://doi.org/10.1124/MOLPHARM.121.000475

    Article  CAS  PubMed  Google Scholar 

  179. Do, P. M., Varanasi, L., Fan, S., Li, C., Kubacka, I., Newman, V., … Martinez, L. A. (2012). Mutant p53 cooperates with ETS2 to promote etoposide resistance. Genes & Development, 26(8), 830–845. https://doi.org/10.1101/GAD.181685.111

  180. Tsai, M. S., Weng, S. H., Chen, H. J., Chiu, Y. F., Huang, Y. C., Tseng, S. C., … Lin, Y. W. (2012). Inhibition of p38 MAPK-dependent excision repair cross-complementing 1 expression decreases the DNA repair capacity to sensitize lung cancer cells to etoposide. Molecular Cancer Therapeutics, 11(3), 561–571. https://doi.org/10.1158/1535-7163.MCT-11-0684/83259/AM/INHIBITION-OF-P38-MAPK-DEPENDENT-EXCISION-REPAIR

  181. Honda, K. (2015). The biological role of actinin-4 (ACTN4) in malignant phenotypes of cancer. Cell and Bioscience, 5(1), 1–9. https://doi.org/10.1186/S13578-015-0031-0/FIGURES/2

    Article  Google Scholar 

  182. Kriger, D., Novitskaya, K., Vasileva, G., Lomert, E., Aksenov, N. D., Barlev, N. A., & Tentler, D. (2022). Alpha-actnin-4 (ACTN4) selectively affects the DNA double-strand breaks repair in non-small lung carcinoma cells. Biology Direct, 17(1), 1–13. https://doi.org/10.1186/S13062-022-00354-6/FIGURES/6

    Article  Google Scholar 

  183. Xu, C., Du, Z., Ren, S., Liang, X., & Li, H. (2020). MiR-129-5p sensitization of lung cancer cells to etoposide-induced apoptosis by reducing YWHAB. Journal of Cancer, 11(4), 858. https://doi.org/10.7150/JCA.35410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Faller, B. A., & Pandit, T. N. (2011). Safety and efficacy of vinorelbine in the treatment of non-small cell lung cancer. Clinical Medicine Insights: Oncology, 5, 131–144. https://doi.org/10.4137/CMO.S5074/ASSET/IMAGES/LARGE/10.4137_CMO.S5074-FIG1.JPEG

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Bessho, Y., Oguri, T., Ozasa, H., Uemura, T., Sakamoto, H., Miyazaki, M., … Ueda, R. (2009). ABCC10/MRP7 is associated with vinorelbine resistance in non-small cell lung cancer. Oncology Reports, 21(1), 263–268. https://doi.org/10.3892/OR_00000217/HTML

  186. Tamari, S., Menju, T., Toyazaki, T., Miyamoto, H., Chiba, N., Noguchi, M., … Date, H. (2022). Nrf2/p-Fyn/ABCB1 axis accompanied by p-Fyn nuclear accumulation plays pivotal roles in vinorelbine resistance in non-small cell lung cancer. Oncology Reports, 48(4), 1–12. https://doi.org/10.3892/OR.2022.8386

  187. Stuckler, D., Singhal, J., Singhal, S. S., Yadav, S., Awasthi, Y. C., & Awasthi, S. (2005). RLIP76 transports vinorelbine and mediates drug resistance in non-small cell lung cancer. Cancer Research, 65(3), 991–998. https://doi.org/10.1158/0008-5472.991.65.3

    Article  CAS  PubMed  Google Scholar 

  188. Sève, P., Mackey, J. R., Isaac, S., Trédan, O., Souquet, P. J., Pérol, M., … Dumontet, C. (2005). cN-II expression predicts survival in patients receiving gemcitabine for advanced non-small cell lung cancer. Lung Cancer, 49(3), 363–370. https://doi.org/10.1016/J.LUNGCAN.2005.04.008

  189. Bepler, G., Kusmartseva, I., Sharma, S., Gautam, A., Cantor, A., Sharma, A., & Simon, G. (2006). RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. Journal of Clinical Oncology, 24, 4731–4737. https://doi.org/10.1200/JCO.2006.06.1101

    Article  CAS  PubMed  Google Scholar 

  190. Chen, P., Wu, J. N., Shu, Y., Jiang, H. G., Zhao, X. H., Qian, H., … Li, J. (2018). Gemcitabine resistance mediated by ribonucleotide reductase M2 in lung squamous cell carcinoma is reversed by GW8510 through autophagy induction. Clinical Science, 132(13), 1417–1433. https://doi.org/10.1042/CS20180010

  191. Zhang, H. H., Zhang, Z. Y., Che, C. L., Mei, Y. F., & Shi, Y. Z. (2013). Array analysis for potential biomarker of gemcitabine identification in non-small cell lung cancer cell lines. International Journal of Clinical and Experimental Pathology, 6(9), 1734. Retrieved from /pmc/articles/PMC3759480/

  192. Hu, B. D., Guo, J., Ye, Y. Z., Du, T., Cheng, C. S., Jiang, Q., … Zhang, Y. B. (2018). Specific inhibitor of Notch-3 enhances the sensitivity of NSCLC cells to gemcitabine. Oncology Reports, 40(1), 155–164. https://doi.org/10.3892/OR.2018.6448/HTML

  193. Ikeda, R., Vermeulen, L. C., Lau, E., Jiang, Z., Sachidanandam, K., Yamada, K., & Kolesar, J. M. (2011). Isolation and characterization of gemcitabine-resistant human non-small cell lung cancer A549 cells. International Journal of Oncology, 38(2), 513–519. https://doi.org/10.3892/IJO.2010.866/HTML

    Article  CAS  PubMed  Google Scholar 

  194. Tsai, M. S., Kuo, Y. H., Chiu, Y. F., Su, Y. C., & Lin, Y. W. (2010). Down-regulation of Rad51 expression overcomes drug resistance to gemcitabine in human non-small-cell lung cancer cells. Journal of Pharmacology and Experimental Therapeutics, 335(3), 830–840. https://doi.org/10.1124/JPET.110.173146

    Article  CAS  PubMed  Google Scholar 

  195. Qu, Y., Yang, Y., Liu, B., & Xiao, W. (2010). Comparative proteomic profiling identified sorcin being associated with gemcitabine resistance in non-small cell lung cancer. Medical Oncology, 27(4), 1303–1308. https://doi.org/10.1007/S12032-009-9379-5/FIGURES/3

    Article  CAS  PubMed  Google Scholar 

  196. Wang, Y., Liang, H. X., Zhang, C. M., Zou, M., Zou, B. B., Wei, W., & Hu, W. (2020). FOXO3/TRIM22 axis abated the antitumor effect of gemcitabine in non-small cell lung cancer via autophagy induction. Translational Cancer Research, 9(2), 937. https://doi.org/10.21037/TCR.2019.12.33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Xiang L, Wang Y, Lan J, Na F, Wu S, Gong Y, … Xie G. (2022). HIF-1-dependent heme synthesis promotes gemcitabine resistance in human non-small cell lung cancers via enhanced ABCB6 expression. Cellular and Molecular Life Sciences, 79(6), 343.

  198. Jiang, S., Zou, J., Dong, J., Shi, H., Chen, J., Li, Y., … Li, W. (2023). Lower SLC7A2 expression is associated with enhanced multidrug resistance, less immune infiltrates and worse prognosis of NSCLC. Cell Communication and Signaling, 21(1), 1–15. https://doi.org/10.1186/S12964-022-01023-X/TABLES/1

  199. Chen, W., Tan, X., Yang, Q., Fang, Z., & Xu, Y. (2022). MALAT1 enhances gemcitabine resistance in non-small cell lung cancer cells by directly affecting miR-27a-5p/PBOV1 axis. Cellular Signalling, 94, 110326. https://doi.org/10.1016/J.CELLSIG.2022.110326

    Article  CAS  PubMed  Google Scholar 

  200. Wei, F., Ma, C., Zhou, T., Dong, X., Luo, Q., Geng, L., … Liu, Y. (2017). Exosomes derived from gemcitabine-resistant cells transfer malignant phenotypic traits via delivery of miRNA-222–3p. Molecular Cancer, 16(1), 1–14. https://doi.org/10.1186/S12943-017-0694-8/FIGURES/5

  201. Liang, A. L., Du, S. L., Zhang, B., Zhang, J., Ma, X., Wu, C. Y., & Liu, Y. J. (2019). Screening miRNAs associated with resistance gemcitabine from exosomes in A549 lung cancer cells. Cancer Management and Research, 11, 6311. https://doi.org/10.2147/CMAR.S209149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Bian, W. G., Zhou, X. N., Song, S., Chen, H. T., Shen, Y., & Chen, P. (2021). Reduced miR-363-3p expression in non-small cell lung cancer is associated with gemcitabine resistance via targeting of CUL4A. European Review for Medical and Pharmacological Sciences, 25(21), 6444–6444. https://doi.org/10.26355/EURREV_202111_27133

    Article  PubMed  Google Scholar 

  203. Tanino, R., Tsubata, Y., Harashima, N., Harada, M., & Isobe, T. (2018). Novel drug-resistance mechanisms of pemetrexed-treated non-small cell lung cancer. Oncotarget, 9(24), 16807. https://doi.org/10.18632/ONCOTARGET.24704

    Article  PubMed  PubMed Central  Google Scholar 

  204. Fukuda, S., Oguri, T., Kunii, E., Sone, K., Uemura, T., Takakuwa, O., … Niimi, A. (2016). A folylpoly-γ-glutamate synthase single nucleotide polymorphism associated with response to pemetrexed treatment combined with platinum for non-small cell lung cancer. Lung Cancer, 102, 15–20. https://doi.org/10.1016/J.LUNGCAN.2016.10.006

  205. Shimizu, T., Nakagawa, Y., Takahashi, N., & Hashimoto, S. (2016). Thymidylate synthase gene amplification predicts pemetrexed resistance in patients with advanced non-small cell lung cancer. Clinical and Translational Oncology, 18(1), 107–112. https://doi.org/10.1007/S12094-015-1359-Y/FIGURES/4

    Article  CAS  PubMed  Google Scholar 

  206. Uemura, T., Oguri, T., Ozasa, H., Takakuwa, O., Miyazaki, M., Maeno, K., … Ueda, R. (2010). ABCC11/MRP8 confers pemetrexed resistance in lung cancer. Cancer Science, 101(11), 2404–2410. https://doi.org/10.1111/J.1349-7006.2010.01690.X

  207. Yu, Z., Li, X. M., Liu, S. H., Liu, B., Gao, C. H., & Hou, X. (2014). Downregulation of both EGFR and ErbB3 improves the cellular response to pemetrexed in an established pemetrexed-resistant lung adenocarcinoma A549 cell line. Oncology Reports, 31(4), 1818–1824. https://doi.org/10.3892/OR.2014.3027/HTML

    Article  CAS  PubMed  Google Scholar 

  208. Weeks, L. D., Fu, P., & Gerson, S. L. (2013). Uracil-DNA glycosylase expression determines human lung cancer cell sensitivity to pemetrexed. Molecular Cancer Therapeutics, 12(10), 2248–2260. https://doi.org/10.1158/1535-7163.MCT-13-0172/208842/AM/URACIL-DNA-GLYCOSYLASE-EXPRESSION-DETERMINES-HUMAN

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Ko, J. C., Chiu, H. C., Syu, J. J., Chen, C. Y., Jian, Y. T., Huang, Y. J., … Lin, Y. W. (2015). Down-regulation of MSH2 expression by Hsp90 inhibition enhances cytotoxicity affected by tamoxifen in human lung cancer cells. Biochemical and Biophysical Research Communications, 456(1), 506–512. https://doi.org/10.1016/J.BBRC.2014.11.116

  210. Grabauskiene, S., Bergeron, E. J., Chen, G., Chang, A. C., Lin, J., Thomas, D. G., … Reddy, R. M. (2013). CHK1 levels correlate with sensitization to pemetrexed by CHK1 inhibitors in non-small cell lung cancer cells. Lung Cancer, 82(3), 477–484. https://doi.org/10.1016/J.LUNGCAN.2013.09.010

  211. Jiang, C., Liao, J., Yang, F., Jiang, T., Zhang, D., & Xin, Y. (2022). The potential mechanism of HDAC1-catalyzed histone crotonylation of caspase-1 in nonsmall cell lung cancer. Evidence-based Complementary and Alternative Medicine, 2022. https://doi.org/10.1155/2022/5049116

  212. Chang, W. W., Wang, B. Y., Chen, S. H., Chien, P. J., Sheu, G. T., & Lin, C. H. (2022). miR-145-5p targets Sp1 in non-small cell lung cancer cells and links to BMI1 induced pemetrexed resistance and epithelial–mesenchymal transition. International Journal of Molecular Sciences, 23(23), 15352. https://doi.org/10.3390/IJMS232315352/S1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Zheng, F., & Xu, R. (2020). CircPVT1 contributes to chemotherapy resistance of lung adenocarcinoma through miR-145-5p/ABCC1 axis. Biomedicine & Pharmacotherapy, 124, 109828. https://doi.org/10.1016/J.BIOPHA.2020.109828

    Article  CAS  Google Scholar 

  214. Liang, S. Q., Marti, T. M., Dorn, P., Froment, L., Hall, S. R. R., Berezowska, S., … Peng, R. W. (2015). Blocking the epithelial-to-mesenchymal transition pathway abrogates resistance to anti-folate chemotherapy in lung cancer. Cell Death & Disease, 6(7), e1824–e1824. https://doi.org/10.1038/cddis.2015.195

  215. Shi, S.-B., Wang, M., Tian, J., Li, R., Chang, C. X., & Qi, J. L. (2016). MicroRNA 25, microRNA 145, and microRNA 210 as biomarkers for predicting the efficacy of maintenance treatment with pemetrexed in lung adenocarcinoma patients who are negative for epidermal growth factor receptor mutations or anaplastic lymphoma kinase translocations. Translational Research, 170, 1–7. https://doi.org/10.1016/J.TRSL.2015.11.006

    Article  CAS  PubMed  Google Scholar 

  216. Zhao, K., & So, H. C. (2019). Using drug expression profiles and machine learning approach for drug repurposing. Methods in Molecular Biology, 1903, 219–237. https://doi.org/10.1007/978-1-4939-8955-3_13/COVER

    Article  CAS  PubMed  Google Scholar 

  217. Scannell, J. W., Blanckley, A., Boldon, H., & Warrington, B. (2012). Diagnosing the decline in pharmaceutical R&D efficiency. Nature Reviews Drug Discovery, 11(3), 191–200. https://doi.org/10.1038/nrd3681

    Article  CAS  PubMed  Google Scholar 

  218. Wouters, O. J., McKee, M., & Luyten, J. (2020). Estimated research and development investment needed to bring a new medicine to market, 2009–2018. JAMA, 323(9), 844–853. https://doi.org/10.1001/JAMA.2020.1166

    Article  PubMed  PubMed Central  Google Scholar 

  219. Zhang, Z., Zhou, L., Xie, N., Nice, E. C., Zhang, T., Cui, Y., & Huang, C. (2020). Overcoming cancer therapeutic bottleneck by drug repurposing. Signal Transduction and Targeted Therapy, 5(1), 1–25. https://doi.org/10.1038/s41392-020-00213-8

    Article  Google Scholar 

  220. Stachnik, A., Yuen, T., Iqbal, J., Sgobba, M., Gupta, Y., Lu, P., … Zaidi, M. (2014). Repurposing of bisphosphonates for the prevention and therapy of nonsmall cell lung and breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 111(50), 17995–18000. https://doi.org/10.1073/PNAS.1421422111/SUPPL_FILE/PNAS.201421422SI.PDF

  221. Boolell, M., Allen, M. J., Ballard, S. A., Gepi-Attee, S., Muirhead, G. J., Naylor, A. M., … Gingell, C. (1996). Sildenafil: An orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. International Journal of Impotence Research, 8(2), 47–52. Retrieved from https://europepmc.org/article/med/8858389

  222. Parikh, A. B., Kozuch, P., Rohs, N., Becker, D. J., & Levy, B. P. (2017). Metformin as a repurposed therapy in advanced non-small cell lung cancer (NSCLC): Results of a phase II trial. Investigational New Drugs, 35(6), 813–819. https://doi.org/10.1007/S10637-017-0511-7/TABLES/3

    Article  CAS  PubMed  Google Scholar 

  223. Chang, A. (2011). Chemotherapy, chemoresistance and the changing treatment landscape for NSCLC. Lung Cancer, 71(1), 3–10. https://doi.org/10.1016/J.LUNGCAN.2010.08.022

    Article  PubMed  Google Scholar 

  224. Wu, X., Li, F., Wang, X., Li, C., Meng, Q., Wang, C., … Zhu, Z. (2018). Antibiotic bedaquiline effectively targets growth, survival and tumor angiogenesis of lung cancer through suppressing energy metabolism. Biochemical and Biophysical Research Communications, 495(1), 267–272. https://doi.org/10.1016/J.BBRC.2017.10.136

  225. Nappi, L., Aguda, A. H., al Nakouzi, N., Lelj-Garolla, B., Beraldi, E., Lallous, N., … Gleave, M. (2020). Ivermectin inhibits HSP27 and potentiates efficacy of oncogene targeting in tumor models. The Journal of Clinical Investigation, 130(2), 699–714. https://doi.org/10.1172/JCI130819

  226. Li, R., Hu, Z., Sun, S. Y., Chen, Z. G., Owonikoko, T. K., Sica, G. L., … Deng, X. (2013). Niclosamide overcomes acquired resistance to erlotinib through suppression of STAT3 in non-small cell lung cancer. Molecular Cancer Therapeutics, 12(10), 2200–2212. https://doi.org/10.1158/1535-7163.MCT-13-0095/208827/AM/NICLOSAMIDE-OVERCOMES-ACQUIRED-RESISTANCE-TO

  227. Osada, T., Chen, M., Yang, X. Y., Spasojevic, I., Vandeusen, J. B., Hsu, D., … Lyerly, H. K. (2011). Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations. Cancer Research, 71(12), 4172–4182. https://doi.org/10.1158/0008-5472.CAN-10-3978/649773/AM/ANTI-HELMINTH-COMPOUND-NICLOSAMIDE-DOWNREGULATES

  228. Li, X. Q., Yue, C. W., Xu, W. H., Lü, Y. H., Huang, Y. J., Tian, P., & Liu, T. (2020). A milbemycin compound isolated from Streptomyces Sp. FJS31-2 with cytotoxicity and reversal of cisplatin resistance activity in A549/DDP cells. Biomedicine & Pharmacotherapy, 128, 110322. https://doi.org/10.1016/J.BIOPHA.2020.110322

  229. Zhang, Q., Yi, H., Yao, H., Lu, L., He, G., Wu, M., … Deng, X. (2021). Artemisinin derivatives inhibit non-small cell lung cancer cells through induction of ROS-dependent apoptosis/ferroptosis. Journal of Cancer, 12(13), 4075. https://doi.org/10.7150/JCA.57054

  230. Zhang, Y., Wang, Y., Li, Y., Huang, C., Xiao, X., Zhong, Z., … Yang, J. (2022). Dihydroartemisinin and artesunate inhibit aerobic glycolysis via suppressing c-Myc signaling in non-small cell lung cancer. Biochemical Pharmacology, 198, 114941. https://doi.org/10.1016/J.BCP.2022.114941

  231. Cao, D., Chen, D., Xia, J. N., Wang, W. Y., Zhu, G. Y., Chen, L. W., … Li, Y. W. (2022). Artesunate promoted anti-tumor immunity and overcame EGFR-TKI resistance in non-small-cell lung cancer by enhancing oncogenic TAZ degradation. Biomedicine & Pharmacotherapy, 155, 113705. https://doi.org/10.1016/J.BIOPHA.2022.113705

  232. Wang, J. S., Wang, M. J., Lu, X., Zhang, J., Liu, Q. X., Zhou, D., … Zheng, H. (2020). Artesunate inhibits epithelial-mesenchymal transition in non-small-cell lung cancer (NSCLC) cells by down-regulating the expression of BTBD7. Bioengineered, 11(1), 1197–1207. https://doi.org/10.1080/21655979.2020.1834727

  233. Zhao, Y., Jiang, W., Li, B., Yao, Q., Dong, J., Cen, Y., … Zhou, H. (2011). Artesunate enhances radiosensitivity of human non-small cell lung cancer A549 cells via increasing NO production to induce cell cycle arrest at G2/M phase. International Immunopharmacology, 11(12), 2039–2046. https://doi.org/10.1016/J.INTIMP.2011.08.017

  234. Ma, H., Yao, Q., Zhang, A. M., Lin, S., Wang, X. X., Wu, L., … Chen, Z. T. (2011). The effects of artesunate on the expression of EGFR and ABCG2 in A549 human lung cancer cells and a xenograft model. Molecules, 16(12), 10556–10569. https://doi.org/10.3390/MOLECULES161210556

  235. Wang, Z., Wang, Q., He, T., Li, W., Liu, Y., Fan, Y., … Chen, J. (2020). The combination of artesunate and carboplatin exerts a synergistic anti-tumour effect on non-small cell lung cancer. Clinical and Experimental Pharmacology and Physiology, 47(6), 1083–1091. https://doi.org/10.1111/1440-1681.13287

  236. Cai, X., Miao, J., Sun, R., Wang, S., Molina-Vila, M. A., Chaib, I., … Cao, P. (2021). Dihydroartemisinin overcomes the resistance to osimertinib in EGFR-mutant non-small-cell lung cancer. Pharmacological Research, 170, 105701. https://doi.org/10.1016/J.PHRS.2021.105701

  237. Jin, H., Jiang, A. Y., Wang, H., Cao, Y., Wu, Y., & Jiang, X. F. (2017). Dihydroartemisinin and gefitinib synergistically inhibit NSCLC cell growth and promote apoptosis via the Akt/mTOR/STAT3 pathway. Molecular Medicine Reports, 16(3), 3475–3481. https://doi.org/10.3892/MMR.2017.6989/HTML

  238. Qin, Y., Zhang, Q., Lee, S., Zhong, W. long, Liu, Y. rong, Liu, H. juan, … Zhou, H. gang. (2015). Doxycycline reverses epithelial-to-mesenchymal transition and suppresses the proliferation and metastasis of lung cancer cells. Oncotarget, 6(38), 40667. https://doi.org/10.18632/ONCOTARGET.5842

  239. Datta, S., Choudhury, D., Das, A., Mukherjee, D., das Dasgupta, M., Bandopadhyay, S., & Chakrabarti, G. (2019). Autophagy inhibition with chloroquine reverts paclitaxel resistance and attenuates metastatic potential in human nonsmall lung adenocarcinoma A549 cells via ROS mediated modulation of β-catenin pathway. Apoptosis, 24(5–6), 414–433. https://doi.org/10.1007/S10495-019-01526-Y/FIGURES/11

  240. Zhu, J., Cao, K., Zhao, M., Ma, K., Jiang, X., Bai, Y., … Ma, J. (2023). Improvement of ACK1-targeted therapy efficacy in lung adenocarcinoma using chloroquine or bafilomycin A1. Molecular Medicine, 29(1), 1–21. https://doi.org/10.1186/S10020-023-00602-Z/FIGURES/9

  241. Hao, C., Liu, G., & Tian, G. (2019). Autophagy inhibition of cancer stem cells promotes the efficacy of cisplatin against non-small cell lung carcinoma. Therapeutic Advances in Respiratory Disease, 13.

  242. Malhotra, J., Jabbour, S., Orlick, M., Riedlinger, G., Guo, Y., White, E., & Aisner, J. (2019). Phase Ib/II study of hydroxychloroquine in combination with chemotherapy in patients with metastatic non-small cell lung cancer (NSCLC). Cancer Treatment and Research Communications, 21, 100158. https://doi.org/10.1016/J.CTARC.2019.100158

  243. Li, Y., Cao, F., Li, M., Li, P., Yu, Y., Xiang, L., … Yu, X. (2018). Hydroxychloroquine induced lung cancer suppression by enhancing chemo-sensitization and promoting the transition of M2-TAMs to M1-like macrophages. Journal of Experimental and Clinical Cancer Research, 37(1), 1–16. https://doi.org/10.1186/S13046-018-0938-5/FIGURES/7

  244. Li, H., Zhang, Y., Lan, X., Yu, J., Yang, C., Sun, Z., … Yu, D. (2021). Halofuginone sensitizes lung cancer organoids to cisplatin via suppressing PI3K/AKT and MAPK signaling pathways. Frontiers in Cell and Developmental Biology, 9, 3327. https://doi.org/10.3389/FCELL.2021.773048/BIBTEX

  245. Mi, S., Xiang, G., Yuwen, D., Gao, J., Guo, W., Wu, X., … Xu, Q. (2016). Inhibition of autophagy by andrographolide resensitizes cisplatin-resistant non-small cell lung carcinoma cells via activation of the Akt/mTOR pathway. Toxicology and Applied Pharmacology, 310, 78–86. https://doi.org/10.1016/J.TAAP.2016.09.009

  246. Tan, H., Hu, B., Xie, F., Zhu, C., & Cheng, Z. (2021). Anisomycin sensitizes non-small-cell lung cancer cells to chemotherapeutic agents and epidermal growth factor receptor inhibitor via suppressing PI3K/Akt/mTOR. Fundamental & Clinical Pharmacology, 35(5), 822–831. https://doi.org/10.1111/FCP.12641

  247. Ochi, K., Suzawa, K., Tomida, S., Shien, K., Takano, J., Miyauchi, S., … Toyooka, S. (2020). Overcoming epithelial-mesenchymal transition-mediated drug resistance with monensin-based combined therapy in non-small cell lung cancer. Biochemical and Biophysical Research Communications, 529(3), 760–765. https://doi.org/10.1016/J.BBRC.2020.06.077

  248. Koeck, S., Amann, A., Huber, J. M., Gamerith, G., Hilbe, W., & Zwierzina, H. (2016). The impact of metformin and salinomycin on transforming growth factor β-induced epithelial-to-mesenchymal transition in non-small cell lung cancer cell lines. Oncology Letters, 11(4), 2946–2952. https://doi.org/10.3892/OL.2016.4323/HTML

  249. Wu, J. Y., Lin, S. S., Hsu, F. T., & Chung, J. G. (2018). Fluoxetine inhibits DNA repair and NF-ĸB-modulated metastatic potential in non-small cell lung cancer. Anticancer Research, 38(9), 5201–5210. https://doi.org/10.21873/ANTICANRES.12843

  250. ClinicalTrials.gov. (n.d.). US National Library of Medicine. Retrieved December 12, 2021, from https://clinicaltrials.gov/ct2/home

  251. Wang, K., Chen, B., Yin, T., Zhan, Y., Lu, Y., Zhang, Y., … Xiao, J. (2019). N-methylparoxetine blocked autophagic flux and induced apoptosis by activating ROS-MAPK pathway in non-small cell lung cancer cells. International Journal of Molecular Sciences, 20(14), 3415. https://doi.org/10.3390/IJMS20143415

  252. Li, Y.-l., Ding, K., Hu, X., Wu, L.-w., Zhou, D.-m., Rao, M.-j., … Zhang, C. (2019). DYRK1A inhibition suppresses STAT3/EGFR/Met signalling and sensitizes EGFR wild-type NSCLC cells to AZD9291. Journal of Cellular and Molecular Medicine, 23(11), 7427–7437. https://doi.org/10.1111/JCMM.14609

  253. Misri, S., Kaul, K., Mishra, S., Charan, M., Verma, A. K., Barr, M. P., … Ganju, R. K. (2022). Cannabidiol inhibits tumorigenesis in cisplatin-resistant non-small cell lung cancer via TRPV2. Cancers, 14(5), 1181. https://doi.org/10.3390/CANCERS14051181/S1

  254. Milian, L., Mata, M., Alcacer, J., Oliver, M., Sancho-Tello, M., de Llano, J. J. M., … Carda, C. (2020). Cannabinoid receptor expression in non-small cell lung cancer. Effectiveness of tetrahydrocannabinol and cannabidiol inhibiting cell proliferation and epithelial-mesenchymal transition in vitro. PLOS ONE, 15(2), e0228909. https://doi.org/10.1371/JOURNAL.PONE.0228909

  255. Jiang, X., Lu, W., Shen, X., Wang, Q., Lv, J., Liu, M., … Pang, X. (2018). Repurposing sertraline sensitizes non-small cell lung cancer cells to erlotinib by inducing autophagy. JCI Insight, 3(11). https://doi.org/10.1172/JCI.INSIGHT.98921

  256. Yueh, P. F., Lee, Y. H., Chiang, I. T., Chen, W. T., Lan, K. L., Chen, C. H., & Hsu, F. T. (2021). Suppression of EGFR/PKC-δ/NF-κB signaling associated with imipramine-inhibited progression of non-small cell lung cancer. Frontiers in Oncology, 11, 4439. https://doi.org/10.3389/FONC.2021.735183/BIBTEX

  257. Suzuki, S., Okada, M., Kuramoto, K., Takeda, H., Sakaki, H., Watarai, H., … Kitanaka, C. (2016). Aripiprazole, an antipsychotic and partial dopamine agonist, inhibits cancer stem cells and reverses chemoresistance. Anticancer Research, 36(10).

  258. Dong, C., Chen, Y., Li, H., Yang, Y., Zhang, H., Ke, K., … Lin, M. C. M. (2019). The antipsychotic agent flupentixol is a new PI3K inhibitor and potential anticancer drug for lung cancer. International Journal of Biological Sciences, 15(7), 1523. https://doi.org/10.7150/IJBS.32625

  259. Sad, K., Parashar, P., Tripathi, P., Hungyo, H., Sistla, R., Soni, R., & Tandon, V. (2021). Prochlorperazine enhances radiosensitivity of non-small cell lung carcinoma by stabilizing GDP-bound mutant KRAS conformation. Free Radical Biology and Medicine, 177, 299–312. https://doi.org/10.1016/J.FREERADBIOMED.2021.11.001

  260. Fujiwara, R., Taniguchi, Y., Rai, S., Iwata, Y., Fujii, A., Fujimoto, K., … Matsumura, I. (2022). Chlorpromazine cooperatively induces apoptosis with tyrosine kinase inhibitors in EGFR-mutated lung cancer cell lines and restores the sensitivity to gefitinib in T790M-harboring resistant cells. Biochemical and Biophysical Research Communications, 626, 156–166. https://doi.org/10.1016/J.BBRC.2022.08.010

  261. Sudo, M., Mori, S., Madan, V., Yang, H., Leong, G., & Koeffler, H. P. (2015). Short-hairpin RNA library: Identification of therapeutic partners for gefitinib-resistant non-small cell lung cancer. Oncotarget, 6(2), 814. https://doi.org/10.18632/ONCOTARGET.2891

  262. Yeh, C. T., Wu, A. T. H., Chang, P. M. H., Chen, K. Y., Yang, C. N., Yang, S. C., … Huang, C. Y. F. (2013). Trifluoperazine, an antipsychotic agent, inhibits cancer stem cell growth and overcomes drug resistance of lung cancer. American Journal of Respiratory and Critical Care Medicine, 186(11), 1180–1188. https://doi.org/10.1164/RCCM.201207-1180OC

  263. Chen, J., Dexheimer, T. S., Ai, Y., Liang, Q., Villamil, M. A., Inglese, J., … Zhuang, Z. (2011). Selective and cell-active inhibitors of the USP1/UAF1 deubiquitinase complex reverse cisplatin resistance in non-small cell lung cancer cells. Chemistry & Biology, 18(11), 1390–1400. https://doi.org/10.1016/J.CHEMBIOL.2011.08.014

  264. Bessho, Y., Oguri, T., Achiwa, H., Muramatsu, H., Maeda, H., Niimi, T., … Ueda, R. (2006). Role of ABCG2 as a biomarker for predicting resistance to CPT-11/SN-38 in lung cancer. Cancer Science, 97(3), 192–198. https://doi.org/10.1111/J.1349-7006.2006.00164.X

  265. Suzuki, S., Yamamoto, M., Sanomachi, T., Togashi, K., Seino, S., Sugai, A., … Kitanaka, C. (2021). Lurasidone sensitizes cancer cells to osimertinib by inducing autophagy and reduction of survivin. Anticancer Research, 41(9), 4321–4331. https://doi.org/10.21873/ANTICANRES.15237

  266. Juarez, M., Schcolnik-Cabrera, A., & Dueñas-Gonzalez, A. (2018). The multitargeted drug ivermectin: From an antiparasitic agent to a repositioned cancer drug. American Journal of Cancer Research, 8(2), 317. Retrieved from /pmc/articles/PMC5835698/

  267. Dou, Q., Chen, H. N., Wang, K., Yuan, K., Lei, Y., Li, K., … Huang, C. (2016). Ivermectin induces cytostatic autophagy by blocking the PAK1/Akt Axis in breast cancer. Cancer Research, 76(15), 4457–4469. https://doi.org/10.1158/0008-5472.CAN-15-2887/652181/AM/IVERMECTIN-INDUCES-CYTOSTATIC-AUTOPHAGY-BY

  268. Kwon, Y. J., Petrie, K., Leibovitch, B. A., Zeng, L., Mezei, M., Howell, L., … Waxman, S. (2015). Selective inhibition of SIN3 corepressor with avermectins as a novel therapeutic strategy in triple-negative breast cancer. Molecular Cancer Therapeutics, 14(8), 1824–1836. https://doi.org/10.1158/1535-7163.MCT-14-0980-T/86471/AM/SELECTIVE-INHIBITION-OF-SIN3-COREPRESSOR-WITH

  269. Mastrangelo, E., Pezzullo, M., de burghgraeve, T., Kaptein, S., Pastorino, B., Dallmeier, K., … Milani, M. (2012). Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: New prospects for an old drug. Journal of Antimicrobial Chemotherapy, 67(8), 1884–1894. https://doi.org/10.1093/JAC/DKS147

  270. Sharmeen, S., Skrtic, M., Sukhai, M. A., Hurren, R., Gronda, M., Wang, X., … Schimmer, A. D. (2010). The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells. Blood, 116(18), 3593–3603. https://doi.org/10.1182/BLOOD-2010-01-262675

  271. Jiang, L., Wang, P., Sun, Y. J., & Wu, Y. J. (2019). Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-κB pathway. Journal of Experimental and Clinical Cancer Research, 38(1), 1–18. https://doi.org/10.1186/S13046-019-1251-7/FIGURES/8

  272. Draganov, D., Gopalakrishna-Pillai, S., Chen, Y. R., Zuckerman, N., Moeller, S., Wang, C., … Lee, P. P. (2015). Modulation of P2X4/P2X7/Pannexin-1 sensitivity to extracellular ATP via Ivermectin induces a non-apoptotic and inflammatory form of cancer cell death. Scientific Reports, 5(1), 1–17. https://doi.org/10.1038/srep16222

  273. Nishio, M., Sugimachi, K., Goto, H., Wang, J., Morikawa, T., Miyachi, Y., … Suzuki, A. (2016). Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice. Proceedings of the National Academy of Sciences of the United States of America, 113(1), E71–E80. https://doi.org/10.1073/PNAS.1517188113/SUPPL_FILE/PNAS.201517188SI.PDF

  274. Melotti, A., Mas, C., Kuciak, M., Lorente-Trigos, A., Borges, I., & Ruiz i Altaba, A. (2014). The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pathway responses in human cancer. EMBO Molecular Medicine, 6(10), 1263–1278. https://doi.org/10.15252/EMMM.201404084

  275. Chen, W., Mook, R. A., Premont, R. T., & Wang, J. (2018). Niclosamide: Beyond an antihelminthic drug. Cellular Signalling, 41, 89–96. https://doi.org/10.1016/J.CELLSIG.2017.04.001

  276. MacDonald, M. L., Lamerdin, J., Owens, S., Keon, B. H., Bilter, G. K., Shang, Z., … Westwick, J. K. (2006). Identifying off-target effects and hidden phenotypes of drugs in human cells. Nature Chemical Biology, 2(6), 329–337. https://doi.org/10.1038/nchembio790

  277. Wang, A. M., Ku, H. H., Liang, Y. C., Chen, Y. C., Hwu, Y. M., & Yeh, T. S. (2009). The autonomous notch signal pathway is activated by baicalin and baicalein but is suppressed by niclosamide in K562 cells. Journal of Cellular Biochemistry, 106(4), 682–692. https://doi.org/10.1002/JCB.22065

  278. Stewart, R. L., Carpenter, B. L., West, D. S., Knifley, T., Liu, L., Wang, C., … Chen, M. (2016). S100A4 drives non-small cell lung cancer invasion, associates with poor prognosis, and is effectively targeted by the FDA-approved anti-helminthic agent niclosamide. Oncotarget, 7(23), 34630. https://doi.org/10.18632/ONCOTARGET.8969

  279. Ren, X., Duan, L., He, Q., Zhang, Z., Zhou, Y., Wu, D., … Ding, K. (2010). Identification of niclosamide as a new small-molecule inhibitor of the STAT3 signaling pathway. ACS Medicinal Chemistry Letters, 1(9), 454–459. https://doi.org/10.1021/ML100146Z/SUPPL_FILE/ML100146Z_SI_001.PDF

  280. Fonseca, B. D., Diering, G. H., Bidinosti, M. A., Dalal, K., Alain, T., Balgi, A. D., … Roberge, M. (2012). Structure-activity analysis of niclosamide reveals potential role for cytoplasmic pH in control of mammalian target of rapamycin complex 1 (mTORC1) signaling. Journal of Biological Chemistry, 287(21), 17530–17545. https://doi.org/10.1074/JBC.M112.359638/ATTACHMENT/3042AFCE-091F-4D03-A080-07FD8151AE70/MMC1.PDF

  281. Kumar, R., Coronel, L., Somalanka, B., Raju, A., Aning, O. A., An, O., … Cheok, C. F. (2018). Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers. Nature Communications, 9(1), 1–13. https://doi.org/10.1038/s41467-018-05805-1

  282. Chai, W. H., Li, Y. R., Lin, S. H., Chao, Y. H., Chen, C. H., Chan, P. C., & Lin, C. H. (2020). Antihelminthic niclosamide induces autophagy and delayed apoptosis in human non-small lung cancer cells in vitro and in vivo. Anticancer Research, 40(3), 1405–1417. https://doi.org/10.21873/ANTICANRES.14082

  283. Kim, M.-o., Choe, M. H., Yoon, Y. N., Ahn, J., Yoo, M., Jung, K. Y., … Kim, J. S. (2017). Antihelminthic drug niclosamide inhibits CIP2A and reactivates tumor suppressor protein phosphatase 2A in non-small cell lung cancer cells. Biochemical Pharmacology, 144, 78–89. https://doi.org/10.1016/J.BCP.2017.08.009

  284. Lee, S.-l-o, Son, A. R., Ahn, J., & Song, J. Y. (2014). Niclosamide enhances ROS-mediated cell death through c-Jun activation. Biomedicine & Pharmacotherapy, 68(5), 619–624. https://doi.org/10.1016/J.BIOPHA.2014.03.018

  285. You, S., Li, R., Park, D., Xie, M., Sica, G. L., Cao, Y., … Deng, X. (2014). Disruption of STAT3 by niclosamide reverses radioresistance of human lung cancer. Molecular Cancer Therapeutics, 13(3), 606–616. https://doi.org/10.1158/1535-7163.MCT-13-0608/85335/AM/DISRUPTION-OF-STAT3-BY-NICLOSAMIDE-REVERSES

  286. Luo, F., Luo, M., Rong, Q. X., Zhang, H., Chen, Z., Wang, F., … Fu, L. W. (2019). Niclosamide, an antihelmintic drug, enhances efficacy of PD-1/PD-L1 immune checkpoint blockade in non-small cell lung cancer. Journal for ImmunoTherapy of Cancer, 7(1), 1–13. https://doi.org/10.1186/S40425-019-0733-7/FIGURES/7

  287. Caiaffo, V., Oliveira, B. D. R., de Sá, F. B., & Evêncio Neto, J. (2016). Anti-inflammatory, antiapoptotic, and antioxidant activity of fluoxetine. Pharmacology Research & Perspectives, 4(3), e00231. https://doi.org/10.1002/PRP2.231

  288. Koh, S. J., Kim, J. M., Kim, I. K., Kim, N., Jung, H. C., Song, I. S., & Kim, J. S. (2011). Fluoxetine inhibits NF-κB signaling in intestinal epithelial cells and ameliorates experimental colitis and colitis-associated colon cancer in mice. American Journal of Physiology - Gastrointestinal and Liver Physiology, 301(1), 9–19. https://doi.org/10.1152/AJPGI.00267.2010/ASSET/IMAGES/LARGE/ZH30061159410010.JPEG

  289. Chen, W. T., Hsu, F. T., Liu, Y. C., Chen, C. H., Hsu, L. C., & Lin, S. S. (2019). Fluoxetine induces apoptosis through extrinsic/intrinsic pathways and inhibits ERK/NF-κB-modulated anti-apoptotic and invasive potential in hepatocellular carcinoma cells in vitro. International Journal of Molecular Sciences, 20(3), 757. https://doi.org/10.3390/IJMS20030757

  290. Zhao, M., Gao, Y., Wang, L., Liu, S., Han, B., Ma, L., … Wang, X. (2013). Overexpression of integrin-linked kinase promotes lung cancer cell migration and invasion via NF-κB-mediated upregulation of matrix metalloproteinase-9. International Journal of Medical Sciences, 10(8), 995. https://doi.org/10.7150/IJMS.5963

  291. Freire-Garabal, M., Núňez, M. J., Pereiro, D., Riveiro, P., Losada, C., Fernández-Rial, J. C., … Rey-Méndez, M. (1998). Effects of fluoxetine on the development of lung metastases induced by operative stress in rats. Life Sciences, 63(2), PL31–PL38. https://doi.org/10.1016/S0024-3205(98)00253-7

  292. Stepulak, A., Rzeski, W., Sifringer, M., Brocke, K., Gratopp, A., Kupisz, K., … Ikonomidou, C. (2008). Fluoxetine inhibits the extracellular signal regulated kinase pathway and suppresses growth of cancer cells. https://doi.org/10.4161/cbt.7.10.6664, 7(10), 1685–1693. https://doi.org/10.4161/CBT.7.10.6664

  293. Lionta, E., Spyrou, G., K. Vassilatis, D., & Cournia, Z. (n.d.). Structure-based virtual screening for drug discovery: Principles, applications and recent advances. Current Topics in Medicinal Chemistry, 14(16), 1923–1938. https://doi.org/10.2174/1568026614666140929124445

  294. Li, H., Tong, C. W. S., Leung, Y., Wong, M. H., To, K. K. W., & Leung, K. S. (2017). Identification of clinically approved drugs indacaterol and canagliflozin for repurposing to treat epidermal growth factor tyrosine kinase inhibitor-resistant lung cancer. Frontiers in Oncology, 7(NOV), 288. https://doi.org/10.3389/FONC.2017.00288/BIBTEX

  295. Dey, S., Hafkemeyer, P., Pastan, I., & Gottesman, M. M. (1999). A single amino acid residue contributes to distinct mechanisms of inhibition of the human multidrug transporter by stereoisomers of the dopamine receptor antagonist flupentixol †. Biochemistry, 38(20), 6630–6639. https://doi.org/10.1021/BI983038L

Download references

Acknowledgements

The authors thank the management of VIT, Vellore, for their constant encouragement and support as well as for creating the scientific ambience and providing unlimited Wi-Fi connectivity. The authors also thank biorender (https://www.biorender.com/), which enabled us to compile the images incorporated herein.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to P. K. Suresh.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kaur, R., Suresh, P.K. Chemoresistance Mechanisms in Non-Small Cell Lung Cancer—Opportunities for Drug Repurposing. Appl Biochem Biotechnol (2023). https://doi.org/10.1007/s12010-023-04595-7

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12010-023-04595-7

Keywords

Navigation