Abstract
Non-small cell lung cancer (NSCLC), which represents 80–85% of lung cancer cases, is one of the leading causes of human death worldwide. The majority of patients undergo an intensive and invasive treatment regimen, which may include radiotherapy, chemotherapy, targeted therapy, immunotherapy, or a combination of these, depending on disease stage and performance status. Despite advances in therapeutic regimens, the 5-year survival of NSCLC is approximately 20–30%, largely due to diagnosis at advanced stages. Conventional chemotherapy is still the standard treatment option for patients with NSCLC, especially those with advanced disease. However, the emergence of resistance to chemotherapeutic agents (chemoresistance) poses a significant obstacle to the management of patients with NSCLC. Therefore, to develop efficacious chemotherapeutic approaches for NSCLC, it is necessary to understand the mechanisms underlying chemoresistance. Several mechanisms are known to mediate chemoresistance. These include altered cellular targets for chemotherapy, decreased cellular drug concentrations, blockade of chemotherapy-induced cell cycle arrest and apoptosis, acquisition of epithelial–mesenchymal transition and cancer stem cell-like phenotypes, deregulated expression of microRNAs, epigenetic modulation, and the interaction with tumor microenvironments. In this review, we summarize the mechanisms underlying chemoresistance and tumor recurrence in NSCLC and discuss potential strategies to avoid or overcome chemoresistance.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Achiwa H, Oguri T, Sato S, Maeda H, Niimi T, Ueda R (2004) Determinants of sensitivity and resistance to gemcitabine: the roles of human equilibrative nucleoside transporter 1 and deoxycytidine kinase in non-small cell lung cancer. Cancer Sci 95:753–757. https://doi.org/10.1111/j.1349-7006.2004.tb03257.x
Adjei AA, Salavaggione OE, Mandrekar SJ, Dy GK, Ziegler KL, Endo C, Molina JR, Schild SE, Adjei AA (2010) Correlation between polymorphisms of the reduced folate carrier gene (SLC19A1) and survival after pemetrexed-based therapy in non-small cell lung cancer: a North Central Cancer Treatment Group-based exploratory study. J Thorac Oncol 5:1346–1353. https://doi.org/10.1097/JTO.0b013e3181ec18c4
Aguirre-Ghiso JA (2007) Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 7:834–846. https://doi.org/10.1038/nrc2256
Ahmad A, MiY M, Ginnebaugh KR, Li Y, Bao B, Gadgeel SM, Sarkar FH (2013) Inhibition of Hedgehog signaling sensitizes NSCLC cells to standard therapies through modulation of EMT-regulating miRNAs. J Hematol Oncol 6:77. https://doi.org/10.1186/1756-8722-6-77
Albertella MR, Green CM, Lehmann AR, O’Connor MJ (2005) A role for polymerase eta in the cellular tolerance to cisplatin-induced damage. Cancer Res 65:9799–9806. https://doi.org/10.1158/0008-5472.CAN-05-1095
Arevalo E, Castanon E, Lopez I, Salgado J, Collado V, Santisteban M, Rodriguez-Ruiz M, Martin P, Zubiri L, Patino-Garcia A, Rolfo C, Gil-Bazo I (2014) Thymidylate synthase polymorphisms in genomic DNA as clinical outcome predictors in a European population of advanced non-small cell lung cancer patients receiving pemetrexed. J Transl Med 12:98. https://doi.org/10.1186/1479-5876-12-98
Atjanasuppat K, Lirdprapamongkol K, Jantaree P, Svasti J (2015) Non-adherent culture induces paclitaxel resistance in H460 lung cancer cells via ERK-mediated up-regulation of betaIVa-tubulin. Biochem Biophys Res Commun 466:493–498. https://doi.org/10.1016/j.bbrc.2015.09.057
Bai L, Zhu R, Chen Z, Gao L, Zhang X, Wang X, Bai C (2006) Potential role of short hairpin RNA targeting epidermal growth factor receptor in growth and sensitivity to drugs of human lung adenocarcinoma cells. Biochem Pharmacol 71:1265–1271. https://doi.org/10.1016/j.bcp.2005.12.029
Barr MP, Gray SG, Hoffmann AC, Hilger RA, Thomale J, O’Flaherty JD, Fennell DA, Richard D, O’Leary JJ, O’Byrne KJ (2013) Generation and characterisation of cisplatin-resistant non-small cell lung cancer cell lines displaying a stem-like signature. PLoS ONE 8:e54193. https://doi.org/10.1371/journal.pone.0054193
Basu A, Krishnamurthy S (2010) Cellular responses to Cisplatin-induced DNA damage. J Nucleic Acids. https://doi.org/10.4061/2010/201367
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. J Clin Oncol 24:4731–4737. https://doi.org/10.1200/JCO.2006.06.1101
Berghmans T, Dingemans AM, Hendriks LEL, Cadranel J (2020a) Immunotherapy for nonsmall cell lung cancer: a new therapeutic algorithm. Eur Respir J. https://doi.org/10.1183/13993003.01907-2019
Berghmans T, Durieux V, Hendriks LEL, Dingemans AM (2020b) Immunotherapy: from advanced NSCLC to early stages, an evolving concept. Front Med (Lausanne) 7:90. https://doi.org/10.3389/fmed.2020.00090
Bessho Y, Oguri T, Ozasa H, Uemura T, Sakamoto H, Miyazaki M, Maeno K, Sato S, Ueda R (2009) ABCC10/MRP7 is associated with vinorelbine resistance in non-small cell lung cancer. Oncol Rep 21:263–268
Bian WG, Zhou XN, Song S, Chen HT, Shen Y, Chen P (2019) Reduced miR-363-3p expression in non-small cell lung cancer is associated with gemcitabine resistance via targeting of CUL4A. Eur Rev Med Pharmacol Sci 23:649–659. https://doi.org/10.26355/eurrev_201901_16879
Booton R, Ward T, Ashcroft L, Morris J, Heighway J, Thatcher N (2007) ERCC1 mRNA expression is not associated with response and survival after platinum-based chemotherapy regimens in advanced non-small cell lung cancer. J Thorac Oncol 2:902–906. https://doi.org/10.1097/JTO.0b013e318155a637
Boukovinas I, Papadaki C, Mendez P, Taron M, Mavroudis D, Koutsopoulos A, Sanchez-Ronco M, Sanchez JJ, Trypaki M, Staphopoulos E, Georgoulias V, Rosell R, Souglakos J (2008) Tumor BRCA1, RRM1 and RRM2 mRNA expression levels and clinical response to first-line gemcitabine plus docetaxel in non-small-cell lung cancer patients. PLoS ONE 3:e3695. https://doi.org/10.1371/journal.pone.0003695
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424. https://doi.org/10.3322/caac.21492
Catuogno S, Cerchia L, Romano G, Pognonec P, Condorelli G, de Franciscis V (2013) miR-34c may protect lung cancer cells from paclitaxel-induced apoptosis. Oncogene 32:341–351. https://doi.org/10.1038/onc.2012.51
Ceppi P, Novello S, Cambieri A, Longo M, Monica V, Lo Iacono M, Giaj-Levra M, Saviozzi S, Volante M, Papotti M, Scagliotti G (2009) Polymerase eta mRNA expression predicts survival of non-small cell lung cancer patients treated with platinum-based chemotherapy. Clin Cancer Res 15:1039–1045. https://doi.org/10.1158/1078-0432.CCR-08-1227
Ceppi P, Rapa I, Lo Iacono M, Righi L, Giorcelli J, Pautasso M, Bille A, Ardissone F, Papotti M, Scagliotti GV (2012) Expression and pharmacological inhibition of thymidylate synthase and Src kinase in nonsmall cell lung cancer. Int J Cancer 130:1777–1786. https://doi.org/10.1002/ijc.26188
Chatterjee A, Chattopadhyay D, Chakrabarti G (2014) miR-17-5p downregulation contributes to paclitaxel resistance of lung cancer cells through altering beclin1 expression. PLoS ONE 9:e95716. https://doi.org/10.1371/journal.pone.0095716
Chatterjee A, Chattopadhyay D, Chakrabarti G (2015) MiR-16 targets Bcl-2 in paclitaxel-resistant lung cancer cells and overexpression of miR-16 along with miR-17 causes unprecedented sensitivity by simultaneously modulating autophagy and apoptosis. Cell Signal 27:189–203. https://doi.org/10.1016/j.cellsig.2014.11.023
Chen K, Shi W (2016) Autophagy regulates resistance of non-small cell lung cancer cells to paclitaxel. Tumour Biol 37:10539–10544. https://doi.org/10.1007/s13277-016-4929-x
Chen SH, Chang JY (2019) New insights into mechanisms of cisplatin resistance: from tumor cell to microenvironment. Int J Mol Sci. https://doi.org/10.3390/ijms20174136
Chen M, Zhao H (2019) Next-generation sequencing in liquid biopsy: cancer screening and early detection. Hum Genomics 13:34. https://doi.org/10.1186/s40246-019-0220-8
Chen Z, Fillmore CM, Hammerman PS, Kim CF, Wong KK (2014) Non-small-cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer 14:535–546. https://doi.org/10.1038/nrc3775
Chen J, Jiang CC, Jin L, Zhang XD (2016) Regulation of PD-L1: a novel role of pro-survival signalling in cancer. Ann Oncol 27:409–416. https://doi.org/10.1093/annonc/mdv615
Chen B, Tan Y, Liang Y, Li Y, Chen L, Wu S, Xu W, Wang Y, Zhao W, Wu J (2017) Per2 participates in AKT-mediated drug resistance in A549/DDP lung adenocarcinoma cells. Oncol Lett 13:423–428. https://doi.org/10.3892/ol.2016.5430
Chen MJ, Wu DW, Wang GC, Wang YC, Chen CY, Lee H (2018a) MicroRNA-630 may confer favorable cisplatin-based chemotherapy and clinical outcomes in non-small cell lung cancer by targeting Bcl-2. Oncotarget 9:13758–13767. https://doi.org/10.18632/oncotarget.24474
Chen P, Wu J-N, Shu Y, Jiang H-G, Zhao X-H, Qian H, Chen K, Lan T, Chen C-G, Li J (2018b) Gemcitabine resistance mediated by ribonucleotide reductase M2 in lung squamous cell carcinoma is reversed by GW8510 through autophagy induction. Clin Sci 132:1417–1433. https://doi.org/10.1042/cs20180010
Chen J, Liu X, Xu Y, Zhang K, Huang J, Pan B, Chen D, Cui S, Song H, Wang R, Chu X, Zhu X, Chen L (2019a) TFAP2C-activated MALAT1 modulates the chemoresistance of docetaxel-resistant lung adenocarcinoma cells. Mol Ther Nucleic Acids 14:567–582. https://doi.org/10.1016/j.omtn.2019.01.005
Chen X, Zhu H, Ye W, Cui Y, Chen M (2019b) MicroRNA29a enhances cisplatin sensitivity in nonsmall cell lung cancer through the regulation of REV3L. Mol Med Rep 19:831–840. https://doi.org/10.3892/mmr.2018.9723
Chiu LY, Hsin IL, Yang TY, Sung WW, Chi JY, Chang JT, Ko JL, Sheu GT (2017) The ERK-ZEB1 pathway mediates epithelial–mesenchymal transition in pemetrexed resistant lung cancer cells with suppression by vinca alkaloids. Oncogene 36:242–253. https://doi.org/10.1038/onc.2016.195
Cho J, Lee HJ, Hwang SJ, Min HY, Kang HN, Park AY, Hyun SY, Sim JY, Lee HJ, Jang HJ, Suh YA, Hong S, Shin YK, Kim HR, Lee HY (2020a) The interplay between slow-cycling, chemoresistant cancer cells and fibroblasts creates a proinflammatory niche for tumor progression. Cancer Res 80:2257–2272. https://doi.org/10.1158/0008-5472.CAN-19-0631
Cho J, Min HY, Pei H, Wei X, Sim JY, Park SH, Hwang SJ, Lee HJ, Hong S, Shin YK, Lee HY (2020b) The ATF6-EGF pathway mediates the awakening of slow-cycling chemoresistant cells and tumor recurrence by stimulating tumor angiogenesis. Cancers (Basel). https://doi.org/10.3390/cancers12071772
Cho J, Min HY, Lee HJ, Hyun SY, Sim JY, Noh M, Hwang SJ, Park SH, Boo HJ, Lee HJ, Hong S, Park RW, Shin YK, Hung MC, Lee HY (2021) RGS2-mediated translational control mediates cancer cell dormancy and tumor relapse. J Clin Invest. https://doi.org/10.1172/JCI136779
Chou HC, Chen JY, Lin DY, Wen YF, Lin CC, Lin SH, Lin CH, Chung TW, Liao EC, Chen YJ, Wei YS, Tsai YT, Chan HL (2015) Identification of up- and down-regulated proteins in pemetrexed-resistant human lung adenocarcinoma: flavin reductase and calreticulin play key roles in the development of pemetrexed-associated resistance. J Proteome Res 14:4907–4920. https://doi.org/10.1021/acs.jproteome.5b00794
Cruz-Bermudez A, Laza-Briviesca R, Vicente-Blanco RJ, Garcia-Grande A, Coronado MJ, Laine-Menendez S, Palacios-Zambrano S, Moreno-Villa MR, Ruiz-Valdepenas AM, Lendinez C, Romero A, Franco F, Calvo V, Alfaro C, Acosta PM, Salas C, Garcia JM, Provencio M (2019) Cisplatin resistance involves a metabolic reprogramming through ROS and PGC-1alpha in NSCLC which can be overcome by OXPHOS inhibition. Free Radic Biol Med 135:167–181. https://doi.org/10.1016/j.freeradbiomed.2019.03.009
Dalvi MP, Wang L, Zhong R, Kollipara RK, Park H, Bayo J, Yenerall P, Zhou Y, Timmons BC, Rodriguez-Canales J, Behrens C, Mino B, Villalobos P, Parra ER, Suraokar M, Pataer A, Swisher SG, Kalhor N, Bhanu NV, Garcia BA, Heymach JV, Coombes K, Xie Y, Girard L, Gazdar AF, Kittler R, Wistuba II, Minna JD, Martinez ED (2017) Taxane-platin-resistant lung cancers co-develop hypersensitivity to JumonjiC demethylase inhibitors. Cell Rep 19:1669–1684. https://doi.org/10.1016/j.celrep.2017.04.077
Dasari S, Tchounwou PB (2014) Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 740:364–378. https://doi.org/10.1016/j.ejphar.2014.07.025
Dawson MA, Kouzarides T (2012) Cancer epigenetics: from mechanism to therapy. Cell 150:12–27. https://doi.org/10.1016/j.cell.2012.06.013
de Sousa VML, Carvalho L (2018) Heterogeneity in lung cancer. Pathobiology 85:96–107. https://doi.org/10.1159/000487440
de Lucio B, Manuel V, Barrera-Rodriguez R (2005) Characterization of human NSCLC cell line with innate etoposide-resistance mediated by cytoplasmic localization of topoisomerase II alpha. Cancer Sci 96:774–783. https://doi.org/10.1111/j.1349-7006.2005.00111.x
DeBerardinis RJ, Chandel NS (2016) Fundamentals of cancer metabolism. Sci Adv 2:e1600200. https://doi.org/10.1126/sciadv.1600200
Denlinger CE, Rundall BK, Keller MD, Jones DR (2004) Proteasome inhibition sensitizes non-small-cell lung cancer to gemcitabine-induced apoptosis. Ann Thorac Surg 78:1207–1214; discussion 1207–1214. https://doi.org/10.1016/j.athoracsur.2004.04.029
Ding X, Gu Y, Jin M, Guo X, Xue S, Tan C, Huang J, Yang W, Xue M, Zhou Q, Wang W, Zhang Y (2020) The deubiquitinating enzyme UCHL1 promotes resistance to pemetrexed in non-small cell lung cancer by upregulating thymidylate synthase. Theranostics 10:6048–6060. https://doi.org/10.7150/thno.42096
Doi M, Hirayama J, Sassone-Corsi P (2006) Circadian regulator CLOCK is a histone acetyltransferase. Cell 125:497–508. https://doi.org/10.1016/j.cell.2006.03.033
Dong P, Xiong Y, Yue J, Hanley SJB, Watari H (2018) Tumor-intrinsic PD-L1 signaling in cancer initiation, development and treatment: beyond immune evasion. Front Oncol 8:386. https://doi.org/10.3389/fonc.2018.00386
Duan F-G, Wang M-F, Cao Y-B, Dan L, Li R-Z, Fan X-X, Khan I, Lai H-L, Zhang Y-Z, Hsiao WW-L, Yao X-J, Wu Q-B, Liu L, Tang Y-J, Leung EL-H (2019) MicroRNA-421 confers paclitaxel resistance by binding to the KEAP1 3′UTR and predicts poor survival in non-small cell lung cancer. Cell Death Dis 10:821. https://doi.org/10.1038/s41419-019-2031-1
Ebinger S, Ozdemir EZ, Ziegenhain C, Tiedt S, Castro Alves C, Grunert M, Dworzak M, Lutz C, Turati VA, Enver T, Horny HP, Sotlar K, Parekh S, Spiekermann K, Hiddemann W, Schepers A, Polzer B, Kirsch S, Hoffmann M, Knapp B, Hasenauer J, Pfeifer H, Panzer-Grumayer R, Enard W, Gires O, Jeremias I (2016) Characterization of rare, dormant, and therapy-resistant cells in acute lymphoblastic leukemia. Cancer Cell 30:849–862. https://doi.org/10.1016/j.ccell.2016.11.002
Faller BA, Pandit TN (2011) Safety and efficacy of vinorelbine in the treatment of non-small cell lung cancer. Clin Med Insights Oncol 5:131–144. https://doi.org/10.4137/CMO.S5074
Flowers MT, Ntambi JM (2008) Role of stearoyl-coenzyme A desaturase in regulating lipid metabolism. Curr Opin Lipidol 19:248–256. https://doi.org/10.1097/MOL.0b013e3282f9b54d
Fujita Y, Yagishita S, Hagiwara K, Yoshioka Y, Kosaka N, Takeshita F, Fujiwara T, Tsuta K, Nokihara H, Tamura T, Asamura H, Kawaishi M, Kuwano K, Ochiya T (2015) The clinical relevance of the miR-197/CKS1B/STAT3-mediated PD-L1 network in chemoresistant non-small-cell lung cancer. Mol Ther 23:717–727. https://doi.org/10.1038/mt.2015.10
Fukuda S, Oguri T, Kunii E, Sone K, Uemura T, Takakuwa O, Maeno K, Kanemitsu Y, Ohkubo H, Takemura M, Ito Y, Niimi A (2016) A folylpoly-gamma-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
Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, Castedo M, Kroemer G (2012) Molecular mechanisms of cisplatin resistance. Oncogene 31:1869–1883. https://doi.org/10.1038/onc.2011.384
Goetsch L, Gonzalez A, Leger O, Beck A, Pauwels PJ, Haeuw JF, Corvaia N (2005) A recombinant humanized anti-insulin-like growth factor receptor type I antibody (h7C10) enhances the antitumor activity of vinorelbine and anti-epidermal growth factor receptor therapy against human cancer xenografts. Int J Cancer 113:316–328. https://doi.org/10.1002/ijc.20543
Goncalves A, Braguer D, Kamath K, Martello L, Briand C, Horwitz S, Wilson L, Jordan MA (2001) Resistance to Taxol in lung cancer cells associated with increased microtubule dynamics. Proc Natl Acad Sci USA 98:11737–11742. https://doi.org/10.1073/pnas.191388598
Grabauskiene S, Bergeron EJ, Chen G, Chang AC, Lin J, Thomas DG, Giordano TJ, Beer DG, Morgan MA, Reddy RM (2013) CHK1 levels correlate with sensitization to pemetrexed by CHK1 inhibitors in non-small cell lung cancer cells. Lung Cancer 82:477–484. https://doi.org/10.1016/j.lungcan.2013.09.010
Guo Q, Lan F, Yan X, Xiao Z, Wu Y, Zhang Q (2018) Hypoxia exposure induced cisplatin resistance partially via activating p53 and hypoxia inducible factor-1alpha in non-small cell lung cancer A549 cells. Oncol Lett 16:801–808. https://doi.org/10.3892/ol.2018.8767
Han F, Zhang L, Zhou Y, Yi X (2015) Caveolin-1 regulates cell apoptosis and invasion ability in paclitaxel-induced multidrug-resistant A549 lung cancer cells. Int J Clin Exp Pathol 8:8937–8947
Han ML, Zhao YF, Tan CH, Xiong YJ, Wang WJ, Wu F, Fei Y, Wang L, Liang ZQ (2016) Cathepsin L upregulation-induced EMT phenotype is associated with the acquisition of cisplatin or paclitaxel resistance in A549 cells. Acta Pharmacol Sin 37:1606–1622. https://doi.org/10.1038/aps.2016.93
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. https://doi.org/10.1016/j.cell.2011.02.013
Hanauske A, Chen V, Paoletti P, Niyikiza C (2001) Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors. Oncologist 6(4):363–373
Hande KR (1998) Etoposide: four decades of development of a topoisomerase II inhibitor. Eur J Cancer 34:1514–1521. https://doi.org/10.1016/s0959-8049(98)00228-7
Hirano G, Izumi H, Kidani A, Yasuniwa Y, Han B, Kusaba H, Akashi K, Kuwano M, Kohno K (2010) Enhanced expression of PCAF endows apoptosis resistance in cisplatin-resistant cells. Mol Cancer Res 8:864–872. https://doi.org/10.1158/1541-7786.MCR-09-0458
Holleman A, Chung I, Olsen RR, Kwak B, Mizokami A, Saijo N, Parissenti A, Duan Z, Voest EE, Zetter BR (2011) miR-135a contributes to paclitaxel resistance in tumor cells both in vitro and in vivo. Oncogene 30:4386–4398. https://doi.org/10.1038/onc.2011.148
Hong S, Won YJ, Park YR, Jung KW, Kong HJ, Lee ES, Community of Population-Based Regional Cancer R (2020) Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2017. Cancer Res Treat 52:335–350. https://doi.org/10.4143/crt.2020.206
Hongmei C, Kinsie A, Duane DM, Wei L (2019) Recent advances in elucidating paclitaxel resistance mechanisms in non-small cell lung cancer and strategies to overcome drug resistance. Curr Med Chem 26:1–22. https://doi.org/10.2174/0929867326666191016113631
Horibe S, Matsuda A, Tanahashi T, Inoue J, Kawauchi S, Mizuno S, Ueno M, Takahashi K, Maeda Y, Maegouchi T, Murakami Y, Yumoto R, Nagai J, Takano M (2015) Cisplatin resistance in human lung cancer cells is linked with dysregulation of cell cycle associated proteins. Life Sci 124:31–40. https://doi.org/10.1016/j.lfs.2015.01.011
Hosomi Y, Morita S, Sugawara S, Kato T, Fukuhara T, Gemma A, Takahashi K, Fujita Y, Harada T, Minato K, Takamura K, Hagiwara K, Kobayashi K, Nukiwa T, Inoue A, Group ftN-EJS (2020) Gefitinib alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study. J Clin Oncol 38:115–123. https://doi.org/10.1200/jco.19.01488
Hou X-f, Fan Q-x, Wang L-x, Lu S-x (2009) Role of metallothionein1h in cisplatin resistance of non-small cell lung cancer cells. Chin J Cancer Res 21:247–254. https://doi.org/10.1007/s11670-009-0247-9
Hovelmann S, Beckers TL, Schmidt M (2004) Molecular alterations in apoptotic pathways after PKB/Akt-mediated chemoresistance in NCI H460 cells. Br J Cancer 90:2370–2377. https://doi.org/10.1038/sj.bjc.6601876
Hsin IL, Chiu LY, Ou CC, Wu WJ, Sheu GT, Ko JL (2020) CD133 inhibition via autophagic degradation in pemetrexed-resistant lung cancer cells by GMI, a fungal immunomodulatory protein from Ganoderma microsporum. Br J Cancer 123:449–458. https://doi.org/10.1038/s41416-020-0885-8
Hu BD, Guo J, Ye YZ, Du T, Cheng CS, Jiang Q, Liu RN, Zhang YB (2018) Specific inhibitor of Notch3 enhances the sensitivity of NSCLC cells to gemcitabine. Oncol Rep 40:155–164. https://doi.org/10.3892/or.2018.6448
Huang Z, Wu T, Liu AY, Ouyang G (2015) Differentiation and transdifferentiation potentials of cancer stem cells. Oncotarget 6:39550–39563. https://doi.org/10.18632/oncotarget.6098
Huang CH, Motes HC, Sharma S, Kevern J, Borrego-Diaz E, Sharma M (2017) Abstract 1481: determination of microRNA profile in lung cancer cell line treated with chemotherapy cisplatin (C), pemetrexed (P) or PC with bevacizumab (B) and its implication in resistance. Cancer Res 77:1481–1481. https://doi.org/10.1158/1538-7445.Am2017-1481
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. J Exp Clin Cancer Res 38:180. https://doi.org/10.1186/s13046-019-1166-3
Ibanez de Caceres I, Cortes-Sempere M, Moratilla C, Machado-Pinilla R, Rodriguez-Fanjul V, Manguan-Garcia C, Cejas P, Lopez-Rios F, Paz-Ares L, de CastroCarpeno J, Nistal M, Belda-Iniesta C, Perona R (2010) IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-small-cell lung cancer. Oncogene 29:1681–1690. https://doi.org/10.1038/onc.2009.454
Igarashi T, Izumi H, Uchiumi T, Nishio K, Arao T, Tanabe M, Uramoto H, Sugio K, Yasumoto K, Sasaguri Y, Wang KY, Otsuji Y, Kohno K (2007) Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines. Oncogene 26:4749–4760. https://doi.org/10.1038/sj.onc.1210289
Ikeda R, Vermeulen LC, Lau E, Jiang Z, Sachidanandam K, Yamada K, Kolesar JM (2011) Isolation and characterization of gemcitabine-resistant human non-small cell lung cancer A549 cells. Int J Oncol 38:513–519. https://doi.org/10.3892/ijo.2010.866
Inamura K (2017) Lung cancer: understanding its molecular pathology and the 2015 WHO classification. Front Oncol 7:193. https://doi.org/10.3389/fonc.2017.00193
Inoue Y, Matsumoto H, Yamada S, Kawai K, Suemizu H, Gika M, Takanami I, Nakamura M, Iwazaki M (2010) ATP7B expression is associated with in vitro sensitivity to cisplatin in non-small cell lung cancer. Oncol Lett 1:279–282. https://doi.org/10.3892/ol_00000049
Jemal A, Thun MJ, Ries LA, Howe HL, Weir HK, Center MM, Ward E, Wu XC, Eheman C, Anderson R, Ajani UA, Kohler B, Edwards BK (2008) Annual report to the nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst 100:1672–1694. https://doi.org/10.1093/jnci/djn389
Jia Y, Xie J (2015) Promising molecular mechanisms responsible for gemcitabine resistance in cancer. Genes Dis 2:299–306. https://doi.org/10.1016/j.gendis.2015.07.003
Jia R, Wang C (2020) MiR-29b-3p reverses cisplatin resistance by targeting COL1A1 in non-small-cell lung cancer A549/DDP cells. Cancer Manag Res 12:2559–2566. https://doi.org/10.2147/CMAR.S246625
Jin L, Chun J, Pan C, Li D, Lin R, Alesi GN, Wang X, Kang HB, Song L, Wang D, Zhang G, Fan J, Boggon TJ, Zhou L, Kowalski J, Qu CK, Steuer CE, Chen GZ, Saba NF, Boise LH, Owonikoko TK, Khuri FR, Magliocca KR, Shin DM, Lonial S, Kang S (2018) MAST1 drives cisplatin resistance in human cancers by rewiring cRaf-independent MEK activation. Cancer Cell 34(315–330):e317. https://doi.org/10.1016/j.ccell.2018.06.012
Jordan MA, Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4:253–265. https://doi.org/10.1038/nrc1317
Kaewpiboon C, Srisuttee R, Malilas W, Moon J, Oh S, Jeong HG, Johnston RN, Assavalapsakul W, Chung YH (2015) Upregulation of Stat1-HDAC4 confers resistance to etoposide through enhanced multidrug resistance 1 expression in human A549 lung cancer cells. Mol Med Rep 11:2315–2321. https://doi.org/10.3892/mmr.2014.2949
Kanintronkul Y, Worayuthakarn R, Thasana N, Winayanuwattikun P, Pattanapanyasat K, Surarit R, Ruchirawat S, Svasti J (2011) Overcoming multidrug resistance in human lung cancer with novel benzo[a]quinolizin-4-ones. Anticancer Res 31:921–927
Kavallaris M, Burkhart CA, Horwitz SB (1999) Antisense oligonucleotides to class III beta-tubulin sensitize drug-resistant cells to Taxol. Br J Cancer 80:1020–1025. https://doi.org/10.1038/sj.bjc.6690507
Kelland L (2007) The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 7:573–584. https://doi.org/10.1038/nrc2167
Kim SO, Jeong JY, Kim MR, Cho HJ, Ju JY, Kwon YS, Oh IJ, Kim KS, Kim YI, Lim SC, Kim YC (2008) Efficacy of gemcitabine in patients with non-small cell lung cancer according to promoter polymorphisms of the ribonucleotide reductase M1 gene. Clin Cancer Res 14:3083–3088. https://doi.org/10.1158/1078-0432.CCR-07-4591
Kim ES, Tang XM, Peterson DR, Kilari D, Chow CW, Fujimoto J, Kalhor N, Swisher SG, Stewart DJ, Wistuba II, Siddik ZH (2014) Copper transporter CTR1 expression and tissue platinum concentration in non-small cell lung cancer. Lung Cancer 85:88–93. https://doi.org/10.1016/j.lungcan.2014.04.005
Kim KW, Lee SJ, Kim WY, Seo JH, Lee HY (2017) How can we treat cancer disease not cancer cells? Cancer Res Treat 49:1–9. https://doi.org/10.4143/crt.2016.606
Kim YA, Lee YR, Park J, Oh IH, Kim H, Yoon SJ, Park K (2020) Socioeconomic burden of cancer in Korea from 2011 to 2015. Cancer Res Treat 52:896–906. https://doi.org/10.4143/crt.2019.398
Koh V, Kwan HY, Tan WL, Mah TL, Yong WP (2016) Knockdown of POLA2 increases gemcitabine resistance in lung cancer cells. BMC Genomics 17:1029. https://doi.org/10.1186/s12864-016-3322-x
Koh H, Park H, Chandimali N, Huynh DL, Zhang JJ, Ghosh M, Gera M, Kim N, Bak Y, Yoon DY, Park YH, Kwon T, Jeong DK (2017) MicroRNA-128 suppresses paclitaxel-resistant lung cancer by inhibiting MUC1-C and BMI-1 in cancer stem cells. Oncotarget 8:110540–110551. https://doi.org/10.18632/oncotarget.22818
Konstantinov SM, Berger MR (2008) Alkylating agents. In: Offermanns S, Rosenthal W (eds) Encyclopedia of molecular pharmacology. Springer, Berlin, pp 53–57. https://doi.org/10.1007/978-3-540-38918-7_178
Lee SH (2019) Chemotherapy for lung cancer in the era of personalized medicine. Tuberc Respir Dis (Seoul) 82:179–189. https://doi.org/10.4046/trd.2018.0068
Lee CT, Seol JY, Lee SY, Park KH, Han SJ, Yoo CG, Han SK, Shim YS, Kim YW (2003) The effect of adenovirus-IkappaBalpha transduction on the chemosensitivity of lung cancer cell line with resistance to cis-diamminedichloroplatinum(II)(cisplatin) and doxorubicin(adriamycin). Lung Cancer 41:199–206. https://doi.org/10.1016/s0169-5002(03)00227-7
Lee SH, Noh KB, Lee JS, Lee EJ, Min KH, Hur GY, Lee SH, Lee SY, Kim JH, Lee SY, Shin C, Shim JJ, Kim CH, Kang KH, In KH (2013) Thymidylate synthase and ERCC1 as predictive markers in patients with pulmonary adenocarcinoma treated with pemetrexed and cisplatin. Lung Cancer 81:102–108. https://doi.org/10.1016/j.lungcan.2013.03.002
Lemjabbar-Alaoui H, Hassan OU, Yang YW, Buchanan P (2015) Lung cancer: biology and treatment options. Biochim Biophys Acta 1856:189–210. https://doi.org/10.1016/j.bbcan.2015.08.002
Li ZH, Qiu MZ, Zeng ZL, Luo HY, Wu WJ, Wang F, Wang ZQ, Zhang DS, Li YH, Xu RH (2012) Copper-transporting P-type adenosine triphosphatase (ATP7A) is associated with platinum-resistance in non-small cell lung cancer (NSCLC). J Transl Med 10:21. https://doi.org/10.1186/1479-5876-10-21
Li H, Zhang P, Sun X, Sun Y, Shi C, Liu H, Liu X (2015a) MicroRNA-181a regulates epithelial–mesenchymal transition by targeting PTEN in drug-resistant lung adenocarcinoma cells. Int J Oncol 47:1379–1392. https://doi.org/10.3892/ijo.2015.3144
Li LT, Jiang G, Chen Q, Zheng JN (2015b) Ki67 is a promising molecular target in the diagnosis of cancer (review). Mol Med Rep 11:1566–1572. https://doi.org/10.3892/mmr.2014.2914
Li W, Wang W, Ding M, Zheng X, Ma S, Wang X (2016) MiR-1244 sensitizes the resistance of non-small cell lung cancer A549 cell to cisplatin. Cancer Cell Int 16:30. https://doi.org/10.1186/s12935-016-0305-6
Li C, Zhao X, Yang Y, Liu S, Liu Y, Li X (2018) Interleukin-22 (IL-22) regulates apoptosis of paclitaxel-resistant non-small cell lung cancer cells through C-Jun N-terminal kinase signaling pathway. Med Sci Monit 24:2750–2757. https://doi.org/10.12659/MSM.907336
Liang SQ, Marti TM, Dorn P, Froment L, Hall SR, Berezowska S, Kocher G, Schmid RA, Peng RW (2015) Blocking the epithelial-to-mesenchymal transition pathway abrogates resistance to anti-folate chemotherapy in lung cancer. Cell Death Dis 6:e1824. https://doi.org/10.1038/cddis.2015.195
Liang AL, Du SL, Zhang B, Zhang J, Ma X, Wu CY, Liu YJ (2019a) Screening miRNAs associated with resistance gemcitabine from exosomes in A549 lung cancer cells. Cancer Manag Res 11:6311–6321. https://doi.org/10.2147/CMAR.S209149
Liang J, Lu T, Chen Z, Zhan C, Wang Q (2019b) Mechanisms of resistance to pemetrexed in non-small cell lung cancer. Transl Lung Cancer Res 8:1107–1118. https://doi.org/10.21037/tlcr.2019.10.14
Lin X, Liao Y, Chen X, Long D, Yu T, Shen F (2016) Regulation of oncoprotein 18/stathmin signaling by ERK concerns the resistance to taxol in nonsmall cell lung cancer cells. Cancer Biother Radiopharm 31:37–43. https://doi.org/10.1089/cbr.2015.1921
Liu YP, Yang CJ, Huang MS, Yeh CT, Wu AT, Lee YC, Lai TC, Lee CH, Hsiao YW, Lu J, Shen CN, Lu PJ, Hsiao M (2013) Cisplatin selects for multidrug-resistant CD133+ cells in lung adenocarcinoma by activating Notch signaling. Cancer Res 73:406–416. https://doi.org/10.1158/0008-5472.CAN-12-1733
Liu J, Xing Y, Rong L (2018a) miR-181 regulates cisplatin-resistant non-small cell lung cancer via downregulation of autophagy through the PTEN/PI3K/AKT pathway. Oncol Rep 39:1631–1639. https://doi.org/10.3892/or.2018.6268
Liu Q, Yu S, Zhao W, Qin S, Chu Q, Wu K (2018b) EGFR-TKIs resistance via EGFR-independent signaling pathways. Mol Cancer 17:53. https://doi.org/10.1186/s12943-018-0793-1
Liu Z, Lin H, Gan Y, Cui C, Zhang B, Gu L, Zhou J, Zhu G, Deng D (2019) P16 methylation leads to paclitaxel resistance of advanced non-small cell lung cancer. J Cancer 10:1726–1733. https://doi.org/10.7150/jca.26482
Liu Y, Huber RM, Kiefl R, Tufman A, Kauffmann-Guerrero D (2020) Hedgehog pathway activation might mediate pemetrexed resistance in NSCLC cells. Anticancer Res 40:1451–1458. https://doi.org/10.21873/anticanres.14087
Lord RV, Brabender J, Gandara D, Alberola V, Camps C, Domine M, Cardenal F, Sanchez JM, Gumerlock PH, Taron M, Sanchez JJ, Danenberg KD, Danenberg PV, Rosell R (2002) Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res 8:2286–2291
Lu C, Xie Z, Peng Q (2017) MiRNA-107 enhances chemosensitivity to paclitaxel by targeting antiapoptotic factor Bcl-w in non small cell lung cancer. Am J Cancer Res 7:1863–1873
Luo YH, Luo L, Wampfler JA, Wang Y, Liu D, Chen YM, Adjei AA, Midthun DE, Yang P (2019) 5-year overall survival in patients with lung cancer eligible or ineligible for screening according to US Preventive Services Task Force criteria: a prospective, observational cohort study. Lancet Oncol 20:1098–1108. https://doi.org/10.1016/S1470-2045(19)30329-8
Martin LP, Hamilton TC, Schilder RJ (2008) Platinum resistance: the role of DNA repair pathways. Clin Cancer Res 14:1291–1295. https://doi.org/10.1158/1078-0432.CCR-07-2238
Maschek G, Savaraj N, Priebe W, Braunschweiger P, Hamilton K, Tidmarsh GF, De Young LR, Lampidis TJ (2004) 2-deoxy-d-glucose increases the efficacy of adriamycin and paclitaxel in human osteosarcoma and non-small cell lung cancers in vivo. Cancer Res 64:31–34. https://doi.org/10.1158/0008-5472.can-03-3294
Meyers DE, Bryan PM, Banerji S, Morris DG (2018) Targeting the PD-1/PD-L1 axis for the treatment of non-small-cell lung cancer. Curr Oncol 25:e324–e334. https://doi.org/10.3747/co.25.3976
Miyamoto N, Izumi H, Noguchi T, Nakajima Y, Ohmiya Y, Shiota M, Kidani A, Tawara A, Kohno K (2008) Tip60 is regulated by circadian transcription factor clock and is involved in cisplatin resistance. J Biol Chem 283:18218–18226. https://doi.org/10.1074/jbc.M802332200
Morgan KM, Fischer BS, Lee FY, Shah JJ, Bertino JR, Rosenfeld J, Singh A, Khiabanian H, Pine SR (2017) Gamma secretase inhibition by BMS-906024 enhances efficacy of paclitaxel in lung adenocarcinoma. Mol Cancer Ther 16:2759–2769. https://doi.org/10.1158/1535-7163.MCT-17-0439
Mortality GBD, Causes of Death (2016) Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388:1459–1544. https://doi.org/10.1016/S0140-6736(16)31012-1
Moyer AM, Sun Z, Batzler AJ, Li L, Schaid DJ, Yang P, Weinshilboum RM (2010) Glutathione pathway genetic polymorphisms and lung cancer survival after platinum-based chemotherapy. Cancer Epidemiol Biomark Prev 19:811–821. https://doi.org/10.1158/1055-9965.EPI-09-0871
Muz B, de la Puente P, Azab F, Azab AK (2015) The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckl) 3:83–92. https://doi.org/10.2147/HP.S93413
Obrist F, Michels J, Durand S, Chery A, Pol J, Levesque S, Joseph A, Astesana V, Pietrocola F, Wu GS, Castedo M, Kroemer G (2018) Metabolic vulnerability of cisplatin-resistant cancers. EMBO J. https://doi.org/10.15252/embj.201798597
O’Byrne KJ, Barr MP, Gray SG (2011) The role of epigenetics in resistance to Cisplatin chemotherapy in lung cancer. Cancers (Basel) 3:1426–1453. https://doi.org/10.3390/cancers3011426
Oguri T, Ozasa H, Uemura T, Bessho Y, Miyazaki M, Maeno K, Maeda H, Sato S, Ueda R (2008) MRP7/ABCC10 expression is a predictive biomarker for the resistance to paclitaxel in non-small cell lung cancer. Mol Cancer Ther 7:1150–1155. https://doi.org/10.1158/1535-7163.MCT-07-2088
Ojima I, Lichtenthal B, Lee S, Wang C, Wang X (2016) Taxane anticancer agents: a patent perspective. Expert Opin Ther Pat 26:1–20. https://doi.org/10.1517/13543776.2016.1111872
Olaussen KA, Postel-Vinay S (2016) Predictors of chemotherapy efficacy in non-small-cell lung cancer: a challenging landscape. Ann Oncol 27:2004–2016. https://doi.org/10.1093/annonc/mdw321
Orr GA, Verdier-Pinard P, McDaid H, Horwitz SB (2003) Mechanisms of Taxol resistance related to microtubules. Oncogene 22:7280–7295. https://doi.org/10.1038/sj.onc.1206934
Osarogiagbon RU, Cappuzzo F, Ciuleanu T, Leon L, Klughammer B (2015) Erlotinib therapy after initial platinum doublet therapy in patients with EGFR wild type non-small cell lung cancer: results of a combined patient-level analysis of the NCIC CTG BR.21 and SATURN trials. Transl Lung Cancer Res 4:465–474. https://doi.org/10.3978/j.issn.2218-6751.2015.07.17
Paez D, Labonte MJ, Bohanes P, Zhang W, Benhanim L, Ning Y, Wakatsuki T, Loupakis F, Lenz HJ (2012) Cancer dormancy: a model of early dissemination and late cancer recurrence. Clin Cancer Res 18:645–653. https://doi.org/10.1158/1078-0432.CCR-11-2186
Pan X, Chen Y, Shen Y, Tantai J (2019) Knockdown of TRIM65 inhibits autophagy and cisplatin resistance in A549/DDP cells by regulating miR-138-5p/ATG7. Cell Death Dis 10:429. https://doi.org/10.1038/s41419-019-1660-8
Park SH, Seong MA, Lee HY (2016) p38 MAPK-induced MDM2 degradation confers paclitaxel resistance through p53-mediated regulation of EGFR in human lung cancer cells. Oncotarget 7:8184–8199. https://doi.org/10.18632/oncotarget.6945
Park KS, Kim HK, Lee JH, Choi YB, Park SY, Yang SH, Kim SY, Hong KM (2010) Transglutaminase 2 as a cisplatin resistance marker in non-small cell lung cancer. J Cancer Res Clin Oncol 136:493–502. https://doi.org/10.1007/s00432-009-0681-6
Pei K, Zhu JJ, Wang CE, Xie QL, Guo JY (2016) MicroRNA-185-5p modulates chemosensitivity of human non-small cell lung cancer to cisplatin via targeting ABCC1. Eur Rev Med Pharmacol Sci 20:4697–4704
Piljic Burazer M, Mladinov S, Matana A, Kuret S, Bezic J, Glavina Durdov M (2019) Low ERCC1 expression is a good predictive marker in lung adenocarcinoma patients receiving chemotherapy based on platinum in all TNM stages—a single-center study. Diagn Pathol 14:105. https://doi.org/10.1186/s13000-019-0885-2
Pisanu ME, Noto A, De Vitis C, Morrone S, Scognamiglio G, Botti G, Venuta F, Diso D, Jakopin Z, Padula F, Ricci A, Mariotta S, Giovagnoli MR, Giarnieri E, Amelio I, Agostini M, Melino G, Ciliberto G, Mancini R (2017) Blockade of Stearoyl-CoA-desaturase 1 activity reverts resistance to cisplatin in lung cancer stem cells. Cancer Lett 406:93–104. https://doi.org/10.1016/j.canlet.2017.07.027
Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9:265–273. https://doi.org/10.1038/nrc2620
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. Med Oncol 27:1303–1308. https://doi.org/10.1007/s12032-009-9379-5
Qu Y, Dou B, Tan H, Feng Y, Wang N, Wang D (2019) Tumor microenvironment-driven non-cell-autonomous resistance to antineoplastic treatment. Mol Cancer 18:69. https://doi.org/10.1186/s12943-019-0992-4
Ranganathan AC, Adam AP, Zhang L, Aguirre-Ghiso JA (2006) Tumor cell dormancy induced by p38SAPK and ER-stress signaling: an adaptive advantage for metastatic cells? Cancer Biol Ther 5:729–735. https://doi.org/10.4161/cbt.5.7.2968
Rijo-Ferreira F, Takahashi JS (2019) Genomics of circadian rhythms in health and disease. Genome Med 11:82. https://doi.org/10.1186/s13073-019-0704-0
Rossi A, Ricciardi S, Maione P, de Marinis F, Gridelli C (2009) Pemetrexed in the treatment of advanced non-squamous lung cancer. Lung Cancer 66:141–149. https://doi.org/10.1016/j.lungcan.2009.06.006
Sarin N, Engel F, Kalayda GV, Mannewitz M, Cinatl J Jr, Rothweiler F, Michaelis M, Saafan H, Ritter CA, Jaehde U, Frotschl R (2017) Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest. PLoS ONE 12:e0181081. https://doi.org/10.1371/journal.pone.0181081
Scagliotti GV, Selvaggi G (2006) Antimetabolites and cancer: emerging data with a focus on antifolates. Expert Opin Ther Pat 16:189–200. https://doi.org/10.1517/13543776.16.2.189
Scheff RJ, Schneider BJ (2013) Non-small-cell lung cancer: treatment of late stage disease: chemotherapeutics and new frontiers. Semin Intervent Radiol 30:191–198. https://doi.org/10.1055/s-0033-1342961
Seve P, Mackey JR, Isaac S, Tredan O, Souquet PJ, Perol M, Cass C, Dumontet C (2005) cN-II expression predicts survival in patients receiving gemcitabine for advanced non-small cell lung cancer. Lung Cancer 49:363–370. https://doi.org/10.1016/j.lungcan.2005.04.008
Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ (2007) The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 8:239–245. https://doi.org/10.1038/ni1443
Shen W, Pang H, Liu J, Zhou J, Zhang F, Liu L, Ma N, Zhang N, Zhang H, Liu L (2014) Epithelial–mesenchymal transition contributes to docetaxel resistance in human non-small cell lung cancer. Oncol Res 22:47–55. https://doi.org/10.3727/096504014X14098532393473
Shen H, Wang L, Ge X, Jiang CF, Shi ZM, Li DM, Liu WT, Yu X, Shu YQ (2016) MicroRNA-137 inhibits tumor growth and sensitizes chemosensitivity to paclitaxel and cisplatin in lung cancer. Oncotarget 7:20728–20742. https://doi.org/10.18632/oncotarget.8011
Shen M, Xu Z, Xu W, Jiang K, Zhang F, Ding Q, Xu Z, Chen Y (2019) Inhibition of ATM reverses EMT and decreases metastatic potential of cisplatin-resistant lung cancer cells through JAK/STAT3/PD-L1 pathway. J Exp Clin Cancer Res 38:149. https://doi.org/10.1186/s13046-019-1161-8
Shi SB, Wang M, Tian J, Li R, Chang CX, Qi JL (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. Transl Res 170:1–7. https://doi.org/10.1016/j.trsl.2015.11.006
Shibue T, Weinberg RA (2017) EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol 14:611–629. https://doi.org/10.1038/nrclinonc.2017.44
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. Clin Transl Oncol 18:107–112. https://doi.org/10.1007/s12094-015-1359-y
Shimomura M, Yaoi T, Itoh K, Kato D, Terauchi K, Shimada J, Fushiki S (2012) Drug resistance to paclitaxel is not only associated with ABCB1 mRNA expression but also with drug accumulation in intracellular compartments in human lung cancer cell lines. Int J Oncol 40:995–1004. https://doi.org/10.3892/ijo.2011.1297
Shintani Y, Fujiwara A, Kimura T, Kawamura T, Funaki S, Minami M, Okumura M (2016) IL-6 secreted from cancer-associated fibroblasts mediates chemoresistance in NSCLC by increasing epithelial–mesenchymal transition signaling. J Thorac Oncol 11:1482–1492. https://doi.org/10.1016/j.jtho.2016.05.025
Si W, Shen J, Zheng H, Fan W (2019) The role and mechanisms of action of microRNAs in cancer drug resistance. Clin Epigenet 11:25. https://doi.org/10.1186/s13148-018-0587-8
Silva MM, Rocha CRR, Kinker GS, Pelegrini AL, Menck CFM (2019) The balance between NRF2/GSH antioxidant mediated pathway and DNA repair modulates cisplatin resistance in lung cancer cells. Sci Rep 9:17639. https://doi.org/10.1038/s41598-019-54065-6
Sosa MS, Avivar-Valderas A, Bragado P, Wen HC, Aguirre-Ghiso JA (2011) ERK1/2 and p38alpha/beta signaling in tumor cell quiescence: opportunities to control dormant residual disease. Clin Cancer Res 17:5850–5857. https://doi.org/10.1158/1078-0432.CCR-10-2574
Sosa MS, Bragado P, Aguirre-Ghiso JA (2014) Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer 14:611–622. https://doi.org/10.1038/nrc3793
Sosa Iglesias V, Giuranno L, Dubois LJ, Theys J, Vooijs M (2018) Drug resistance in non-small cell lung cancer: a potential for NOTCH targeting? Front Oncol 8:267. https://doi.org/10.3389/fonc.2018.00267
Spiliotaki M, Markomanolaki H, Mela M, Mavroudis D, Georgoulias V, Agelaki S (2011) Targeting the insulin-like growth factor I receptor inhibits proliferation and VEGF production of non-small cell lung cancer cells and enhances paclitaxel-mediated anti-tumor effect. Lung Cancer 73:158–165. https://doi.org/10.1016/j.lungcan.2010.11.010
Stewart DJ (2007) Mechanisms of resistance to cisplatin and carboplatin. Crit Rev Oncol Hematol 63:12–31. https://doi.org/10.1016/j.critrevonc.2007.02.001
Stuckler D, Singhal J, Singhal SS, Yadav S, Awasthi YC, Awasthi S (2005) RLIP76 transports vinorelbine and mediates drug resistance in non-small cell lung cancer. Cancer Res 65:991–998
Sui X, Chen R, Wang Z, Huang Z, Kong N, Zhang M, Han W, Lou F, Yang J, Zhang Q, Wang X, He C, Pan H (2013) Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis 4:e838–e838. https://doi.org/10.1038/cddis.2013.350
Sui C, Meng F, Li Y, Jiang Y (2015) miR-148b reverses cisplatin-resistance in non-small cell cancer cells via negatively regulating DNA (cytosine-5)-methyltransferase 1(DNMT1) expression. J Transl Med 13:132. https://doi.org/10.1186/s12967-015-0488-y
Sui H, Ma N, Wang Y, Li H, Liu X, Su Y, Yang J (2018) Anti-PD-1/PD-L1 therapy for non-small-cell lung cancer: toward personalized medicine and combination strategies. J Immunol Res 2018:6984948. https://doi.org/10.1155/2018/6984948
Sun H, Zhu A, Zhou X, Wang F (2017) Suppression of pyruvate dehydrogenase kinase-2 re-sensitizes paclitaxel-resistant human lung cancer cells to paclitaxel. Oncotarget 8:52642–52650. https://doi.org/10.18632/oncotarget.16991
Sun DM, Tang BF, Li ZX, Guo HB, Cheng JL, Song PP, Zhao X (2018) MiR-29c reduces the cisplatin resistance of non-small cell lung cancer cells by negatively regulating the PI3K/Akt pathway. Sci Rep 8:8007. https://doi.org/10.1038/s41598-018-26381-w
Sun CY, Nie J, Huang JP, Zheng GJ, Feng B (2019) Targeting STAT3 inhibition to reverse cisplatin resistance. Biomed Pharmacother 117:109135. https://doi.org/10.1016/j.biopha.2019.109135
Takebe N, Miele L, Harris PJ, Jeong W, Bando H, Kahn M, Yang SX, Ivy SP (2015) Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol 12:445–464. https://doi.org/10.1038/nrclinonc.2015.61
Tan Z, Luo X, Xiao L, Tang M, Bode AM, Dong Z, Cao Y (2016) The role of PGC1alpha in cancer metabolism and its therapeutic implications. Mol Cancer Ther 15:774–782. https://doi.org/10.1158/1535-7163.MCT-15-0621
Tanino R, Tsubata Y, Harashima N, Harada M, Isobe T (2018) Novel drug-resistance mechanisms of pemetrexed-treated non-small cell lung cancer. Oncotarget 9:16807–16821. https://doi.org/10.18632/oncotarget.24704
Tao L, Huang G, Wang R, Pan Y, He Z, Chu X, Song H, Chen L (2016) Cancer-associated fibroblasts treated with cisplatin facilitates chemoresistance of lung adenocarcinoma through IL-11/IL-11R/STAT3 signaling pathway. Sci Rep 6:38408. https://doi.org/10.1038/srep38408
Toschi L, Finocchiaro G, Bartolini S, Gioia V, Cappuzzo F (2005) Role of gemcitabine in cancer therapy. Future Oncol 1:7–17. https://doi.org/10.1517/14796694.1.1.7
Tsai MS, Kuo YH, Chiu YF, Su YC, Lin YW (2010) Down-regulation of Rad51 expression overcomes drug resistance to gemcitabine in human non-small-cell lung cancer cells. J Pharmacol Exp Ther 335:830–840. https://doi.org/10.1124/jpet.110.173146
Tung CL, Chiu HC, Jian YJ, Jian YT, Chen CY, Syu JJ, Wo TY, Huang YJ, Tseng SC, Lin YW (2014) Down-regulation of MSH2 expression by an Hsp90 inhibitor enhances pemetrexed-induced cytotoxicity in human non-small-cell lung cancer cells. Exp Cell Res 322:345–354. https://doi.org/10.1016/j.yexcr.2014.02.002
Uemura T, Oguri T, Ozasa H, Takakuwa O, Miyazaki M, Maeno K, Sato S, Ueda R (2010) ABCC11/MRP8 confers pemetrexed resistance in lung cancer. Cancer Sci 101:2404–2410. https://doi.org/10.1111/j.1349-7006.2010.01690.x
Valcourt JR, Lemons JM, Haley EM, Kojima M, Demuren OO, Coller HA (2012) Staying alive: metabolic adaptations to quiescence. Cell Cycle 11:1680–1696. https://doi.org/10.4161/cc.19879
Vilmar A, Sorensen JB (2009) Excision repair cross-complementation group 1 (ERCC1) in platinum-based treatment of non-small cell lung cancer with special emphasis on carboplatin: a review of current literature. Lung Cancer 64:131–139. https://doi.org/10.1016/j.lungcan.2008.08.006
Waldman AD, Fritz JM, Lenardo MJ (2020) A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol. https://doi.org/10.1038/s41577-020-0306-5
Wang R, Huang J, Feng B, De W, Chen L (2012) Identification of ING4 (inhibitor of growth 4) as a modulator of docetaxel sensitivity in human lung adenocarcinoma. Mol Med 18:874–886. https://doi.org/10.2119/molmed.2011.00230
Wang L, Liu X, Ren Y, Zhang J, Chen J, Zhou W, Guo W, Wang X, Chen H, Li M, Yuan X, Zhang X, Yang J, Wu C (2017) Cisplatin-enriching cancer stem cells confer multidrug resistance in non-small cell lung cancer via enhancing TRIB1/HDAC activity. Cell Death Dis 8:e2746. https://doi.org/10.1038/cddis.2016.409
Wang H, Wang L, Zhang G, Lu C, Chu H, Yang R, Zhao G (2018) MALAT1/miR-101-3p/MCL1 axis mediates cisplatin resistance in lung cancer. Oncotarget 9:7501–7512. https://doi.org/10.18632/oncotarget.23483
Wang L, Li X, Ren Y, Geng H, Zhang Q, Cao L, Meng Z, Wu X, Xu M, Xu K (2019a) Cancer-associated fibroblasts contribute to cisplatin resistance by modulating ANXA3 in lung cancer cells. Cancer Sci 110:1609–1620. https://doi.org/10.1111/cas.13998
Wang Y, Li F, Ma D, Gao Y, Li R, Gao Y (2019b) MicroRNA608 sensitizes nonsmall cell lung cancer cells to cisplatin by targeting TEAD2. Mol Med Rep 20:3519–3526. https://doi.org/10.3892/mmr.2019.10616
Wang H, Chen J, Zhang S, Zheng X, Xie S, Mao J, Cai Y, Lu X, Hu L, Shen J, Chai K, Chen W (2020a) MiR-223 regulates autophagy associated with cisplatin resistance by targeting FBXW7 in human non-small cell lung cancer. Cancer Cell Int 20:258. https://doi.org/10.1186/s12935-020-01284-x
Wang Y, Liang H-X, Zhang C-M, Zou M, Zou B-B, Wei W, Hu W (2020b) FOXO3/TRIM22 axis abated the antitumor effect of gemcitabine in non-small cell lung cancer via autophagy induction. Transl Cancer Res 9:937–948
Watanabe M, Masada Y, Hashida S, Ohtsuka T, Suzawa K, Maki Y, Yamamoto H, Soh J, Asano H, Tsukuda K, Toyooka S, Miyoshi S (2015) Abstract 358: the role of GDF-15 on docetaxel resistance in lung cancer. Cancer Res 75:358–358. https://doi.org/10.1158/1538-7445.AM2015-358
Weeks LD, Fu P, Gerson SL (2013) Uracil-DNA glycosylase expression determines human lung cancer cell sensitivity to pemetrexed. Mol Cancer Ther 12:2248–2260. https://doi.org/10.1158/1535-7163.MCT-13-0172
Wei F, Ma C, Zhou T, Dong X, Luo Q, Geng L, Ding L, Zhang Y, Zhang L, Li N, Li Y, Liu Y (2017) Exosomes derived from gemcitabine-resistant cells transfer malignant phenotypic traits via delivery of miRNA-222-3p. Mol Cancer 16:132. https://doi.org/10.1186/s12943-017-0694-8
Wertz IE, Kusam S, Lam C, Okamoto T, Sandoval W, Anderson DJ, Helgason E, Ernst JA, Eby M, Liu J, Belmont LD, Kaminker JS, O’Rourke KM, Pujara K, Kohli PB, Johnson AR, Chiu ML, Lill JR, Jackson PK, Fairbrother WJ, Seshagiri S, Ludlam MJ, Leong KG, Dueber EC, Maecker H, Huang DC, Dixit VM (2011) Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature 471:110–114. https://doi.org/10.1038/nature09779
Wu HM, Jiang ZF, Ding PS, Shao LJ, Liu RY (2015a) Hypoxia-induced autophagy mediates cisplatin resistance in lung cancer cells. Sci Rep 5:12291. https://doi.org/10.1038/srep12291
Wu T, Wang MC, Jing L, Liu ZY, Guo H, Liu Y, Bai YY, Cheng YZ, Nan KJ, Liang X (2015b) Autophagy facilitates lung adenocarcinoma resistance to cisplatin treatment by activation of AMPK/mTOR signaling pathway. Drug Des Dev Ther 9:6421–6431. https://doi.org/10.2147/DDDT.S95606
Wu HM, Shao LJ, Jiang ZF, Liu RY (2016) Gemcitabine-induced autophagy protects human lung cancer cells from apoptotic death. Lung 194:959–966. https://doi.org/10.1007/s00408-016-9936-6
Wu X, Wu Q, Zhou X, Huang J (2019) SphK1 functions downstream of IGF-1 to modulate IGF-1-induced EMT, migration and paclitaxel resistance of A549 cells: a preliminary in vitro study. J Cancer 10:4264–4269. https://doi.org/10.7150/jca.32646
Xiang F, Wu R, Ni Z, Pan C, Zhan Y, Xu J, Meng X, Kang X (2014) MyD88 expression is associated with paclitaxel resistance in lung cancer A549 cells. Oncol Rep 32:1837–1844. https://doi.org/10.3892/or.2014.3433
Xu H, Lv M, Tian X (2009) A review on hemisynthesis, biosynthesis, biological activities, mode of action, and structure-activity relationship of podophyllotoxins: 2003–2007. Curr Med Chem 16:327–349. https://doi.org/10.2174/092986709787002682
Xu X, Jin S, Ma Y, Fan Z, Yan Z, Li W, Song Q, You W, Lyu Z, Song Y, Shi P, Liu Y, Han X, Li L, Li Y, Liu Y, Ye Q (2017) miR-30a-5p enhances paclitaxel sensitivity in non-small cell lung cancer through targeting BCL-2 expression. J Mol Med (Berl) 95:861–871. https://doi.org/10.1007/s00109-017-1539-z
Xu F, Gu J, Lu C, Mao W, Wang L, Zhu Q, Liu Z, Chu Y, Liu R, Ge D (2019) Calpain-2 enhances non-small cell lung cancer progression and chemoresistance to paclitaxel via EGFR-pAKT pathway. Int J Biol Sci 15:127–137. https://doi.org/10.7150/ijbs.28834
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. J Cancer 11:858–866. https://doi.org/10.7150/jca.35410
Yang M, Fan WF, Pu XL, Liu FY, Meng LJ, Wang J (2014) Significance of thymidylate synthase expression for resistance to pemetrexed in pulmonary adenocarcinoma. Oncol Lett 7:227–232. https://doi.org/10.3892/ol.2013.1688
Yang T, Li H, Chen T, Ren H, Shi P, Chen M (2019) LncRNA MALAT1 depressed chemo-sensitivity of NSCLC cells through directly functioning on miR-197-3p/p120 catenin axis. Mol Cells 42:270–283. https://doi.org/10.14348/molcells.2019.2364
Ye Z, Yin S, Su Z, Bai M, Zhang H, Hei Z, Cai S (2016) Downregulation of miR-101 contributes to epithelial–mesenchymal transition in cisplatin resistance of NSCLC cells by targeting ROCK2. Oncotarget 7:37524–37535. https://doi.org/10.18632/oncotarget.6852
Ye L, Pu C, Tang J, Wang Y, Wang C, Qiu Z, Xiang T, Zhang Y, 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. Respir Res 20:106. https://doi.org/10.1186/s12931-019-1071-5
Yokobori T, Yokoyama Y, Mogi A, Endoh H, Altan B, Kosaka T, Yamaki E, Yajima T, Tomizawa K, Azuma Y, Onozato R, Miyazaki T, Tanaka S, Kuwano H (2014) FBXW7 mediates chemotherapeutic sensitivity and prognosis in NSCLCs. Mol Cancer Res 12:32–37. https://doi.org/10.1158/1541-7786.MCR-13-0341
Young LC, Campling BG, Cole SP, Deeley RG, Gerlach JH (2001) Multidrug resistance proteins MRP3, MRP1, and MRP2 in lung cancer: correlation of protein levels with drug response and messenger RNA levels. Clin Cancer Res 7:1798–1804
Yu Z, Li XM, Liu SH, Liu B, Gao CH, Hou X (2014) Downregulation of both EGFR and ErbB3 improves the cellular response to pemetrexed in an established pemetrexedresistant lung adenocarcinoma A549 cell line. Oncol Rep 31:1818–1824. https://doi.org/10.3892/or.2014.3027
Yuan M, Huang LL, Chen JH, Wu J, Xu Q (2019) The emerging treatment landscape of targeted therapy in non-small-cell lung cancer. Signal Transduct Target Ther 4:61. https://doi.org/10.1038/s41392-019-0099-9
Zajicek G (1978) Cancer as a systemic disease. Med Hypotheses 4:193–207. https://doi.org/10.1016/0306-9877(78)90002-6
Zarogoulidis K, Zarogoulidis P, Darwiche K, Boutsikou E, Machairiotis N, Tsakiridis K, Katsikogiannis N, Kougioumtzi I, Karapantzos I, Huang H, Spyratos D (2013) Treatment of non-small cell lung cancer (NSCLC). J Thorac Dis 5(Suppl 4):S389-396. https://doi.org/10.3978/j.issn.2072-1439.2013.07.10
Zeng-Rong N, Paterson J, Alpert L, Tsao MS, Viallet J, Alaoui-Jamali MA (1995) Elevated DNA repair capacity is associated with intrinsic resistance of lung cancer to chemotherapy. Cancer Res 55:4760–4764
Zhang HH, Zhang ZY, Che CL, Mei YF, Shi YZ (2013) Array analysis for potential biomarker of gemcitabine identification in non-small cell lung cancer cell lines. Int J Clin Exp Pathol 6:1734–1746
Zhang J, Liu J, Li H, Wang J (2016a) beta-Catenin signaling pathway regulates cisplatin resistance in lung adenocarcinoma cells by upregulating Bcl-xl. Mol Med Rep 13:2543–2551. https://doi.org/10.3892/mmr.2016.4882
Zhang P, Ma Y, Lv C, Huang M, Li M, Dong B, Liu X, An G, Zhang W, Zhang J, Zhang L, Zhang S, Yang Y (2016b) Upregulation of programmed cell death ligand 1 promotes resistance response in non-small-cell lung cancer patients treated with neo-adjuvant chemotherapy. Cancer Sci 107:1563–1571. https://doi.org/10.1111/cas.13072
Zhang F, Shen M, Yang L, Yang X, Tsai Y, Keng PC, Chen Y, Lee SO, Chen Y (2017a) Simultaneous targeting of ATM and Mcl-1 increases cisplatin sensitivity of cisplatin-resistant non-small cell lung cancer. Cancer Biol Ther 18:606–615. https://doi.org/10.1080/15384047.2017.1345391
Zhang Y, Xu W, Guo H, Zhang Y, He Y, Lee SH, Song X, Li X, Guo Y, Zhao Y, Ding C, Ning F, Ma Y, Lei Q-Y, Hu X, Li S, Guo W (2017b) NOTCH1 signaling regulates self-renewal and platinum chemoresistance of cancer stem–like cells in human non–small cell lung cancer. Can Res 77:3082–3091. https://doi.org/10.1158/0008-5472.Can-16-1633
Zhao Y, Lu H, Yan A, Yang Y, Meng Q, Sun L, Pang H, Li C, Dong X, Cai L (2013) ABCC3 as a marker for multidrug resistance in non-small cell lung cancer. Sci Rep 3:3120. https://doi.org/10.1038/srep03120
Zhao W, Li H, Yang S, Guo D, Chen J, Miao S, Xin Y, Liang M (2019) MicroRNA-152 suppresses cisplatin resistance in A549 cells. Oncol Lett 18:4613–4620. https://doi.org/10.3892/ol.2019.10834
Zhao J, Xue X, Fu W, Dai L, Jiang Z, Zhong S, Deng B, Yin J (2020) Epigenetic activation of FOXF1 confers cancer stem cell properties to cisplatinresistant nonsmall cell lung cancer. Int J Oncol 56:1083–1092. https://doi.org/10.3892/ijo.2020.5003
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. Front Pharmacol 11:343. https://doi.org/10.3389/fphar.2020.00343
Acknowledgements
This work was supported by a grant from the National Research Foundation of Korea (NRF), the Ministry of Science and ICT (MSIT), Republic of Korea (No. NRF-2016R1A3B1908631).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declared that they have no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Min, HY., Lee, HY. Mechanisms of resistance to chemotherapy in non-small cell lung cancer. Arch. Pharm. Res. 44, 146–164 (2021). https://doi.org/10.1007/s12272-021-01312-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-021-01312-y