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Current Cancer Drug Targets

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Mini-Review Article

Elucidation of the Role of the Epigenetic Regulatory Mechanisms of PI3K/Akt/mTOR Signaling Pathway in Human Malignancies

Author(s): Rupali Mohite and Gaurav Doshi*

Volume 24, Issue 3, 2024

Published on: 28 August, 2023

Page: [231 - 244] Pages: 14

DOI: 10.2174/1568009623666230801094826

Price: $65

Abstract

The PI3K/Akt/mTOR pathway modulates cell growth, proliferation, metabolism, and movement. Moreover, significant studies have shown that the genes involved in this pathway are frequently activated in human cancer. Observational and computational modeling of the PI3K/AKt/ mTOR pathway inhibitors has been explored in clinical trials. It has been observed that the effectiveness and safety evidence from clinical studies and various inhibitors of this route have been given FDA approval. In this review article, we focused on the processes behind the overactivation of PI3K/Akt/mTOR signaling in cancer and provided an overview of PI3K/Akt/mTOR inhibitors as either individual drugs or a combination of different doses of drugs for different types of cancer. Furthermore, the review discusses the biological function and activation of the PI3K/AKt/mTOR signaling and their role in the development of cancers. Additionally, we discussed the potential challenges and corresponding prediction biomarkers of response and resistance for PI3K/Akt/m- TOR inhibitor development. The article focuses on the most current breakthroughs in using the PI3K/Akt/mTOR pathway to target certain molecules.

Keywords: Leukemia, PI3K activation, AKT activation, mTOR activation, PI3K/Akt/mTOR inhibitors, cancer.

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Graphical Abstract

[1]
Maria-Magdalena, G. PTEN tumor suppressor network in PI3KAkt pathway control. Genes. Cancer, 2011, 1(12), 1170-1177.
[http://dx.doi.org/10.1186/s12943-019-0954-x] [PMID: 21779440]
[2]
Yang, J; Nie, J; Ma, X; Wei, Y; Peng, Y; Wei, X. Targeting PI3K in cancer: Mechanisms and advances in clinical trials. Mol. Cancer, 2019, 18(1), 26.
[http://dx.doi.org/10.1186/s12943-019-0954-x] [PMID: 30782187]
[3]
Porta, C; Paglino, C; Mosca, A. Targeting PI3K/Akt/mTOR signaling in cancer. Front. Oncol., 2014, 4, 46.
[http://dx.doi.org/10.3389/fonc.2014.00064.] [PMID: 24782981]
[4]
Miricescu, D; Totan, A; Badoiu, SC; Stefani, C; Greabu, M PI3K / Akt/ mTOR signaling pathway in breast cancer: From molecular landscape to clinical aspects. Int. J. Mol. Sci., 2021, 22(1), 173.
[http://dx.doi.org/10.3390/ijms22010173.] [PMID: 33375317]
[5]
Balachandran, C.; Emi, N.; Arun, Y.; Yamamoto, N.; Duraipandiyan, V.; Inaguma, Y.; Okamoto, A.; Ignacimuthu, S.; Al-Dhabi, N.A.; Perumal, P.T. In vitro antiproliferative activity of 2,3-dihydroxy-9,10-anthraquinone induced apoptosis against COLO320 cells through cytochrome c release caspase mediated pathway with PI3K/AKT and COX-2 inhibition. Chem. Biol. Interact., 2016, 249, 23-35.
[http://dx.doi.org/10.1016/j.cbi.2016.02.016] [PMID: 26915975]
[6]
Mahajan, K.; Mahajan, N.P. PI3K-Independent AKt activation in cancers: A treasure trove for novel therapeutics. J. Cell Physiol., 2012, 227(9), 3178-3184.
[http://dx.doi.org/10.1002/jcp.24065.] [PMID: 22307544]
[7]
Song, G; Ouyang, G; Bao, S. The activation of Akt / PKB signaling pathway and cell survival. J. Cell Mol. Med., 2005, 9(1), 59-71.
[8]
Gao, N.; Zhang, Z.; Jiang, B.H.; Shi, X. Role of PI3K/AKT/m-TOR signaling in the cell cycle progression of human prostate cancer. Biochem. Biophys. Res. Commun., 2003, 310(4), 1124-1132.
[http://dx.doi.org/10.1016/j.bbrc.2003.09.132] [PMID: 14559232]
[9]
Liu, X.; Zhang, L.; Yang, L.; Cui, J.; Che, S.; Liu, Y.; Han, J.; An, X.; Cao, B.; Song, Y. miR-34a/c induce caprine endometrial epithelial cell apoptosis by regulating circ-8073/ CEP55 via the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways. J. Cell. Physiol., 2020, 235(12), 10051-10067.
[http://dx.doi.org/10.1002/jcp.29821] [PMID: 32474960]
[10]
Braglia, L.; Zavatti, M.; Vinceti, M.; Martelli, A.M.; Marmiroli, S. Deregulated PTEN/PI3K/AKT/mTOR signaling in prostate cancer: Still a potential druggable target? Biochim. Biophys. Acta Mol. Cell Res., 2020, 1867(9), 118731.
[http://dx.doi.org/10.1016/j.bbamcr.2020.118731] [PMID: 32360668]
[11]
Tan, A.C. Targeting the PI3K / Akt / mTOR pathway in non-small cell lung cancer (NSCLC). Thorac. Cancer, 2020, 11(3), 511-518.
[http://dx.doi.org/10.1111/1759-7714.13328.] [PMID: 31989769]
[12]
Basu, S.; Totty, N.F.; Irwin, M.S.; Sudol, M.; Downward, J. Akt phosphorylates the yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol. Cell, 2003, 11(1), 11-23.
[http://dx.doi.org/10.1016/s1097-2765(02)00776-1.] [PMID: 12535517]
[13]
Xu, F.; Na, L.; Li, Y.; Chen, L. RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours. Cell Biosci., 2020, 10(1), 54.
[http://dx.doi.org/10.1186/s13578-020-00416-0] [PMID: 32266056]
[14]
Álvarez, JB; Andersen, JK mTORC2: The other mTOR in autophagy regulation. Aging Cell, 2021, 20(8), e13431.
[http://dx.doi.org/10.1111/acel.13431.] [PMID: 34250734]
[15]
Fattahi, S.; Amjadi-Moheb, F.; Tabaripour, R.; Ashrafi, G.H.; Akhavan-Niaki, H. PI3K/AKT/mTOR signaling in gastric cancer: Epigenetics and beyond. Life Sci., 2020, 262, 118513.
[http://dx.doi.org/10.1016/j.lfs.2020.118513] [PMID: 33011222]
[16]
Xu, F.; Na, L.; Li, Y.; Chen, L. Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours. Cell Biosci., 2020, 10(1), 54.
[http://dx.doi.org/10.1186/s13578-020-00416-0] [PMID: 32266056]
[17]
Hay, N.; Sonenberg, N. Upstream and downstream of mTOR. Genes Dev., 2004, 18(16), 1926-1945.
[http://dx.doi.org/10.1101/gad.1212704] [PMID: 15314020]
[18]
Peng, Y.; Wang, Y.; Zhou, C.; Mei, W.; Zeng, C. PI3K/Akt/mTOR pathway and its role in cancer therapeutics: Are we making headway? Front. Oncol., 2022, 12, 819128.
[19]
Cerma, K.; Piacentini, F.; Moscetti, L.; Barbolini, M.; Canino, F.; Tornincasa, A. Targeting PI3K/Akt/mTOR pathway in breast cancer: From biology to clinical challenges. Biomedicines, 2023, 11(1), 109.
[20]
Alves, C.L.; Ditzel, H.J. Drugging the PI3K/Akt/mTOR pathway in ER+ breast cancer. Int. J. Mol. Sci., 2023, 24(5), 4522.
[http://dx.doi.org/10.3390/ijms24054522.] [PMID: 36901954]
[21]
Yu, L.; Wei, J.; Liu, P. Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer. Semin. Cancer Biol., 2022, 85, 69-94.
[http://dx.doi.org/10.1016/j.semcancer.2021.06.019] [PMID: 34175443]
[22]
Tian, L.Y.; Smit, D.J.; Jücker, M. The role of PI3K/Akt/mTOR signaling in hepatocellular carcinoma metabolism. Int. J. Mol. Sci., 2023, 24(3), 2652.
[http://dx.doi.org/10.3390/ijms24032652.] [PMID: 36768977]
[23]
Bartlett, J.M.S. Biomarkers and patient selection for PI3K/Akt/m-TOR targeted therapies: Current status and future directions. Clin. Breast Cancer, 2010, 10(Suppl. 3), S86-S95.
[http://dx.doi.org/10.3816/CBC.2010.s.017] [PMID: 21115427]
[24]
Rinne, N.; Christie, E.L.; Ardasheva, A.; Kwok, C.H.; Demchenko, N.; Low, C.; Tralau-Stewart, C.; Fotopoulou, C.; Cunnea, P. Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer, therapeutic treatment options for platinum-resistant ovarian cancer. Cancer Drug Resist., 2021, 4(3), 573-595.
[http://dx.doi.org/10.20517/cdr.2021.05] [PMID: 35582310]
[25]
Ediriweera, M.K.; Tennekoon, K.H.; Samarakoon, S.R. Role of the PI3K/AKT/mTOR signaling pathway in ovarian cancer: Biological and therapeutic significance. Semin. Cancer Biol., 2019, 59, 147-160.
[http://dx.doi.org/10.1016/j.semcancer.2019.05.012] [PMID: 31128298]
[26]
van der Ploeg, P.; Uittenboogaard, A.; Thijs, A.M.J.; Westgeest, H.M.; Boere, I.A.; Lambrechts, S.; van de Stolpe, A.; Bekkers, R.L.M.; Piek, J.M.J. The effectiveness of monotherapy with PI3K/AKT/mTOR pathway inhibitors in ovarian cancer: A meta-analysis. Gynecol. Oncol., 2021, 163(2), 433-444.
[http://dx.doi.org/10.1016/j.ygyno.2021.07.008] [PMID: 34253390]
[27]
Paplomata, E.; O’Regan, R. The PI3K/AKT/mTOR pathway in breast cancer: Targets, trials and biomarkers. Ther. Adv. Med. Oncol., 2014, 6(4), 154-166.
[http://dx.doi.org/10.1177/1758834014530023] [PMID: 25057302]
[28]
Andrikopoulou, A.; Chatzinikolaou, S.; Panourgias, E.; Kaparelou, M.; Liontos, M.; Dimopoulos, M.A.; Zagouri, F. “The emerging role of capivasertib in breast cancer”. Breast, 2022, 63(March), 157-167.
[http://dx.doi.org/10.1016/j.breast.2022.03.018] [PMID: 35398754]
[29]
Macdonald, S.; Oncology, R.; General, M. Targeting PI3K/Akt/m-TOR signaling pathway in breast cancer. J. R. Soc. Med., 2016, 70(8), 515-517.
[30]
Houédé, N.; Pourquier, P. Targeting the genetic alterations of the PI3K–AKT–m-TOR pathway: Its potential use in the treatment of bladder cancers. Pharmacol. Ther., 2015, 145(0), 1-18.
[http://dx.doi.org/10.1016/j.pharmthera.2014.06.004] [PMID: 24929024]
[31]
Dako Agilent Pathology Solutions. PD-L1 IHC 28-8 pharmDx Interpretation Manual, Urothelial Carcinoma; Dako Agilent Pathology Solutions: Santa Clara.: CA, USA, 2017, 32, p. 1655.
[32]
Chen, M.; Gu, J.; Delclos, G.L.; Killary, A.M.; Fan, Z.; Hildebrandt, M.A.T.; Chamberlain, R.M.; Grossman, H.B.; Dinney, C.P.; Wu, X. Genetic variations of the PI3K-AKT-m-TOR pathway and clinical outcome in muscle invasive and metastatic bladder cancer patients. Carcinogenesis, 2010, 31(8), 1387-1391.
[http://dx.doi.org/10.1093/carcin/bgq110] [PMID: 20530239]
[33]
Dako Agilent Pathology Solutions. PD-L1 IHC 28-8 pharmDx Interpretation Manual, Urothelial Carcinoma; Dako Agilent Pathology Solutions: Santa Clara.: CA, USA, 2017, 32, p. 1655.
[34]
Butler, D.E.; Marlein, C.; Walker, H.F.; Frame, F.M.; Mann, V.M.; Simms, M.S.; Davies, B.R.; Collins, A.T.; Maitland, N.J. Inhibition of the PI3K/AKT/m-TOR pathway activates autophagy and compensatory Ras/Raf/MEK/ERK signalling in prostate cancer. Oncotarget, 2017, 8(34), 56698-56713.
[http://dx.doi.org/10.18632/oncotarget.18082] [PMID: 28915623]
[35]
Toren, P.; Zoubeidi, A. Targeting the PI3K/Akt pathway in prostate cancer: Challenges and opportunities (Review). Int. J. Oncol., 2014, 45(5), 1793-1801.
[http://dx.doi.org/10.3892/ijo.2014.2601] [PMID: 25120209]
[36]
Shorning, B.Y.; Dass, M.S.; Smalley, M.J.; Pearson, H.B. The PI3K-Akt-m-TOR pathway and prostate cancer: At the crossroads of AR, MAPK, and WNT signaling. Int. J. Mol. Sci., 2020, 21(12), 4507.
[http://dx.doi.org/10.3390/ijms21124507.] [PMID: 32630372]
[37]
Morgan, TM; Koreckij, TD; Corey, E Targeted therapy for advanced prostate cancer: Inhibition of the PI3K / Akt / m-TOR pathway. Curr. Cancer Drug Targets, 2009, 9(2), 237-249.
[38]
Phase III copanlisib in rituximab-refractory iNHL (CHRONOS-2). NCT02369016, 2015.
[39]
Liu, T.J.; Koul, D.; LaFortune, T.; Tiao, N.; Shen, R.J.; Maira, S.M.; Garcia-Echevrria, C.; Yung, W.K.A. NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas. Mol. Cancer Ther., 2009, 8(8), 2204-2210.
[http://dx.doi.org/10.1158/1535-7163.MCT-09-0160] [PMID: 19671762]
[40]
A Phase 3 Study to determine if RTB101 prevents clinically symptomatic respiratory illness in the elderly. NCT04668352, 2020.
[41]
Rodrigues, D.A.; Sagrillo, F.S.; Fraga, C.A.M.; Duvelisib, A. Duvelisib: A 2018 Novel FDA-approved small molecule inhibiting phosphoinositide 3-kinases. Pharmaceuticals, 2019, 12(2), 69.
[http://dx.doi.org/10.3390/ph12020069] [PMID: 31064155]
[42]
A study of acalabrutinib vs investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab in R/R CLL. NCT02970318, 2023.
[43]
Bird, ST; Tian, F; Flowers, N; Przepiorka, D; Wang, R Idelalisib for treatment of relapsed follicular lymphoma and chronic lymphocytic leukemia a comparison of treatment outcomes in clinical trial participants vs medicare beneficiaries. JAMA Oncol., 2020, 6(2), 248-254.
[44]
Single-arm study With bimiralisib in patients with HNSCC harboring NOTCH1 loss of function mutations (HNSCC). NCT03740100, 2022.
[45]
Study to evaluate the efficacy/safety of IPI-549 in combination with nivolumab in patients with advanced urothelial carcinoma (MARIO-275). NCT03980041, 2022.
[46]
Evaluation of IPI-549 combined with front-line treatments in Pts. With Triple-Negative Breast Cancer or Renal Cell Carcinoma (MARIO-3) (MARIO-3). . NCT03961698, 2022.
[47]
Study to evaluate the efficacy and safety of CUDC-907 in patients With RR DLBCL, including patients With MYC alterations. NCT02674750, 2022.
[48]
CUDC-907 Treatment in people with metastatic and locally advanced thyroid Cancer. NCT03002623, 2018.
[49]
Gedatolisib plus talazoparib in advanced triple negative or BRCA1/2 positive, HER2 negative breast cancers. NCT03911973, 2023.
[50]
Li, J.; Xu, N.; Liu, T.; Huang, J.; Yin, Y.; Mou, H.; Zhang, J.; Wu, L. A phase Ib study of the PI3Kδ inhibitor linperlisib in patients with advanced solid tumors. Clin. Oncol., 2021, 39(S1), 3099-3099.
[51]
Schöffski, P; Cresta, S; Mayer, IA; Wildiers, H; Damian, S; Gendreau, S A phase Ib study of pictilisib ( GDC-0941 ) in combination with paclitaxel, with and without bevacizumab or trastuzumab, and with letrozole in advanced breast cancer. Breast Cancer Res., 2018, 20(1), 109.
[52]
Howes, AL; Chiang, GG; Lang, ES; Ho, CB; Powis, G; Vuori, K. The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures. Mol. Cancer Ther., 2007, 6(9), 2505-2514.
[http://dx.doi.org/10.1158/1535-7163.MCT-06-0698.] [PMID: 17766839]
[53]
Gan, ZY; Fitter, S; Vandyke, K; To, LB; Zannettino, ACW; Martin, SK The effect of the dual PI3K and m-TOR inhibitor BEZ235 on tumour growth and osteolytic bone disease in multiple myeloma. Eur. J. Haematol., 2014, 94(4), 343-54.
[54]
Xie, Y; Shi, X; Sheng, KUO; Han, G; Li, W; Zhao, Q. PI3K / Akt signaling transduction pathway, erythropoiesis and glycolysis in hypoxia (Review). Mol. Med. Rep., 2019, 19(2), 783-791.
[55]
Alzahrani, A.S. PI3K/Akt/m-TOR inhibitors in cancer: At the bench and bedside. Semin. Cancer Biol., 2019, 59, 125-132.
[http://dx.doi.org/10.1016/j.semcancer.2019.07.009] [PMID: 31323288]
[56]
Lindsley, CW; Barnett, SF; Layton, ME; Bilodeau, MT. The PI3K / Akt pathway: Recent progress in the development of ATP-competitive and allosteric Akt kinase inhibitors. Curr. Cancer Drug Targets, 2008, 8(1), 7-18.
[http://dx.doi.org/10.2174/156800908783497096] [PMID: 18288939]
[57]
Papadimitrakopoulou, V; Gandara, DR; Patnaik, A; Richard, D; Olmos, D; Garrett, CR. Anti-tumour activity in RAS-driven tumours by blocking Akt and MEK. Clin. Cancer Res., 2014, 21(4), 739-748.
[58]
Martorana, F.; Motta, G.; Pavone, G.; Motta, L.; Stella, S.; Vitale, S.R.; Manzella, L.; Vigneri, P. AKT Inhibitors: New weapons in the fight against breast cancer? Front. Pharmacol., 2021, 12(April), 662232.
[http://dx.doi.org/10.3389/fphar.2021.662232] [PMID: 33995085]
[59]
Capivasertib + CDK4/6i + fulvestrant for advanced/metastatic HR+/HER2- Breast Cancer (CAPItello-292) (CAPItello-292). NCT04862663, , 2023.
[60]
Fizazi, K.; George, D.J.; De Santis, M.; Clarke, N.; Fay, A.P.; Uemura, H.; Grinsted, L.; Rooney, C.; Verheijen, R.B.; Anjum, R.; Foxley, A.; Morris, T. A phase III trial of capivasertib and abiraterone versus placebo and abiraterone in patients with de novo metastatic hormone-sensitive prostate cancer characterized by PTEN deficiency (CAPItello-281). J. Clin. Oncol., 2021, 39(6_suppl), TPS178.
[http://dx.doi.org/10.1200/JCO.2021.39.6_suppl.TPS178]
[61]
Ahn, D.H.; Li, J.; Wei, L.; Doyle, A.; Marshall, J.L.; Schaaf, L.J.; Phelps, M.A.; Villalona-Calero, M.A.; Bekaii-Saab, T. Results of an abbreviated phase-II study with the Akt inhibitor MK-2206 in patients with advanced biliary cancer. Sci. Rep., 2015, 5(1), 12122.
[http://dx.doi.org/10.1038/srep12122] [PMID: 26161813]
[62]
Coleman, N; Moyers, JT; Harbery, A; Vivanco, I; Yap, TA Clinical development of Akt inhibitors and associated predictive biomarkers to guide patient treatment in cancer medicine. Pharmgenomics Pers. Med., 2021, 14, 1517-1535.
[http://dx.doi.org/10.2147/PGPM.S305068]
[63]
Hua, H; Kong, Q; Zhang, H; Wang, J; Luo, T; Jiang, Y. Targeting mTOR for cancer therapy. J. Hematol. Oncol., 2019, 12(1), 71.
[http://dx.doi.org/10.1186/s13045-019-0754-1]
[64]
Faivre, S; Kroemer, G; Raymond, E. Current development of mTOR inhibitors as anticancer agents. Nat. Rev. Drug Discov., 2006, 5(8), 671-688.
[http://dx.doi.org/10.1038/nrd2062]
[65]
Brachmann, S; Fritsch, C. PI3K and m-TOR inhibitors: A new generation of targeted anticancer agents. Curr. Opin Cell Biol., 2009, 21(2), 194-8.
[66]
Mitsudomi, T; Kobayashi, Y Afatinib in lung cancer harboring EGFR mutation in the LUX-lung trials: Six plus three is greater than seven? Transl. Lung Cancer Res., 2016, 5(4), 446-449.
[http://dx.doi.org/10.21037/tlcr.2016.07.06]
[67]
Oza, AM; Elit, L Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: A trial of the NCIC clinical trials group. J. Clin. Oncol., 2011, 39(24), 3278-3285.
[68]
Chan, A; Moy, B; Mansi, J; Ejlertsen, B; Holmes, FA; Chia, S. Final Ef fi cacy results of neratinib in early-stage breast cancer from the Phase III extenet trial. Clin. Breast Cancer, 2021, 21(1), 80-91.e7..
[69]
Gandhi, L.; Besse, B.; Mazieres, J.; Waqar, S.; Cortot, A.; Barlesi, F. Neratinib ± Temsirolimus in HER2-mutant lung cancers: An international, randomized phase II study J. Thorac. Oncol., 2017, 12(1), S358-S359.
[70]
Zhao, H-F.; Zhao, J.; Shao, W.; Chang-Peng, W.; Zhong-Ping, C.; Shing-Shun, T.; Wei-Ping, L. Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: Current preclinical and clinical development. Mol Cancer, 2017, 16(1), 100.
[71]
Liu, R.; Chen, Y.; Liu, G.; Li, C.; Song, Y.; Cao, Z.; Li, W.; Hu, J.; Lu, C.; Liu, Y. PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers. Cell Death Dis., 2020, 11(9), 797.
[http://dx.doi.org/10.1038/s41419-020-02998-6] [PMID: 32973135]
[72]
Luszczak, S.; Simpson, B.S.; Stopka-Farooqui, U.; Sathyadevan, V.K.; Echeverria, L.M.C.; Kumar, C.; Costa, H.; Haider, A.; Freeman, A.; Jameson, C.; Ratynska, M.; Ben-Salha, I.; Sridhar, A.; Shaw, G.; Kelly, J.D.; Pye, H.; Gately, K.A.; Whitaker, H.C.; Heavey, S. Co-targeting PIM and PI3K/m-TOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer. Sci. Rep., 2020, 10(1), 14380.
[http://dx.doi.org/10.1038/s41598-020-71263-9]
[73]
Liu, Pixu; Cheng, H; Thomas, M.R.; Zhao, J.J. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov., 2011, 8(8), 627-44.
[http://dx.doi.org/10.1038/nrd2926.] [PMID: 19644473]
[74]
Phase 1 and 2 Study of PX-866 and Cetuximab. NCT01252628, 2018.
[75]
Shapiro, GI; Lorusso, P; Cho, DC; Musib, L; Yan, Y; Wongchenko, M A phase Ib open-label dose escalation study of the safety, pharmacokinetics, and pharmacodynamics of cobimetinib (GDC-0973) and ipatasertib (GDC-0068) in patients with locally advanced or metastatic solid tumors. Invest. New Drugs, 2020, 39(1), 163-174.
[http://dx.doi.org/10.1007/s10637-020-00975-6] [PMID: 32737717]
[76]
Akt inhibitor, ipatasertib, with endocrine and CDK 4/6 inhibitor for patients with metastatic breast cancer (TAKTIC). NCT03959891, 2023.
[77]
Howell, S.J.; Casbard, A.; Carucci, M.; Ingarfield, K.; Butler, R.; Morgan, S.; Meissner, M.; Bale, C.; Bezecny, P.; Moon, S.; Twelves, C.; Venkitaraman, R.; Waters, S.; de Bruin, E.C.; Schiavon, G.; Foxley, A.; Jones, R.H. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): Overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial. Lancet Oncol., 2022, 23(7), 851-864.
[http://dx.doi.org/10.1016/S1470-2045(22)00284-4] [PMID: 35671774]
[78]
A study of ipatasertib in combination with atezolizumab and paclitaxel as a treatment for participants with locally advanced or metastatic triple-negative breast cancer. NCT04177108, 2023.
[79]
Ma, C.X.; Sanchez, C.; Gao, F.; Crowder, R.; Naughton, M.; Pluard, T.; Creekmore, A.; Guo, Z.; Hoog, J.; Lockhart, A.C.; Doyle, A.; Erlichman, C.; Ellis, M.J. A Phase I Study of the AKT inhibitor MK-2206 in combination with hormonal therapy in postmenopausal women with estrogen receptor–positive metastatic breast cancer. Clin. Cancer Res., 2016, 22(11), 2650-2658.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-2160] [PMID: 26783290]
[80]
Tolcher, AW; Kurzrock, R; Valero, V; Gonzalez, R; Heist, RS; Tan, AR Phase I dose escalation trial of the oral Akt inhibitor uprosertib in combination with the oral MEK1 / MEK2 inhibitor trametinib in patients with solid tumors. Cancer Chemother. Pharmacol., 2020, 85(4), 673-683.
[81]
Uprosertib, dabrafenib, and trametinib in treating patients with stage IIIC-IV Cancer. NCT01902173, 2020.
[82]
Neratinib with and without temsirolimus for patients with HER2 activating mutations in non-small cell lung cancer. NCT01827267, 2018.
[83]
Chan, A; Moy, B; Mansi, J; Ejlertsen, B; Holmes, FA; Chia, S Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III exteNET trial. Clin. Breast Cancer, 2021, 21(1), 80-91.e7.

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