Targeting apoptosis to manage acquired resistance to third generation EGFR inhibitors

doi:10.1007/s11684-022-0951-0

Front. Med.

2022, Vol. 16

Issue (5) : 701-713 https://doi.org/10.1007/s11684-022-0951-0

REVIEW

Targeting apoptosis to manage acquired resistance to third generation EGFR inhibitors

Shi-Yong Sun(

)

Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA

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Abstract

A significant clinical challenge in lung cancer treatment is management of the inevitable acquired resistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs), such as osimertinib, which have shown remarkable success in the treatment of advanced NSCLC with EGFR activating mutations, in order to achieve maximal response duration or treatment remission. Apoptosis is a major type of programmed cell death tightly associated with cancer development and treatment. Evasion of apoptosis is considered a key hallmark of cancer and acquisition of apoptosis resistance is accordingly a key mechanism of drug acquired resistance in cancer therapy. It has been clearly shown that effective induction of apoptosis is a key mechanism for third generation EGFR-TKIs, particularly osimertinib, to exert their therapeutic efficacies and the development of resistance to apoptosis is tightly associated with the emergence of acquired resistance. Hence, restoration of cell sensitivity to undergo apoptosis using various means promises an effective strategy for the management of acquired resistance to third generation EGFR-TKIs.

Keywords acquired resistance EGFR inhibitor apoptosis lung cancer

Corresponding Author(s): Shi-Yong Sun

Just Accepted Date: 17 August 2022 Online First Date: 22 September 2022 Issue Date: 18 November 2022

Cite this article:

Shi-Yong Sun. Targeting apoptosis to manage acquired resistance to third generation EGFR inhibitors[J]. Front. Med., 2022, 16(5): 701-713.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-022-0951-0
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I5/701

Fig.1 Schema for two major apoptotic pathways. Ligation of death ligands (e.g., TRAIL) with their receptors (e.g., DR5) or death receptor aggregation induces formation of the death-inducing signaling complex (DISC). In the DISC, pro-caspase-8 is recruited through the death adaptor protein FADD and cleaved to generate activated caspase-8. This process is negatively regulated by c-FLIP, a truncated pseudo-protein of pro-caspase-8. Signals that activate BH3 only proapoptotic proteins and/or inhibit Bcl-2 antiapoptotic proteins facilitate the insertion of Bax and Bak protein into mitochondrial membrane, increasing mitochondrial outer membrane permeabilization (MOMP); this leads to cytochrome C (Cyt C) and Smac/DIABLO release from the mitochondria into the cytosol. The released cytochrome C then activates pro-caspase-9 by forming an apoptosome through binding to Apaf-1. Both activated caspase-8 and caspase-9 further cleave downstream effector caspases including pro-caspase-3, -6, and -7, to generate activated caspase-3, -6, and -7 that cleave a variety of substrate proteins such as PARP and cause eventual cell death. Caspase-8 also cleaves the BH3 only protein, Bid, to generate truncated Bid (tBid) that facilitates insertion of Bax into the mitochondrial membrane. Thus, tBid connects the extrinsic and intrinsic apoptotic pathways together. Inhibitors of apoptosis proteins (IAPs) such as XIAP and survivin can bind to caspase-9 and prevent its effect on cleavage of effector caspases, whereas Smac/DIABLO binds to IAPs, allowing free caspase-9 to activate the effector caspases.

Fig.2 Summary of potential molecular mechanisms accounting for induction of apoptosis by osimertinib in EGFRm NSCLC cells and by combinations in resistant EGFRm NSCLC cells. The bold red arrows indicate modulations of key apoptosis-regulatory proteins by osimertinib or combinations, which occur at transcriptional and/or posttranslational levels.

Tab.1 Ongoing clinical trials for osimertinib combined with an apoptosis-inducing agent and an agent that leads to enhanced induction of apoptosis

1	RL Siegel, KD Miller, HE Fuchs, A Jemal. Cancer statistics, 2022. CA Cancer J Clin 2022; 72( 1): 7– 33 https://doi.org/10.3322/caac.21708 pmid: 35020204
2	H Sung, J Ferlay, RL Siegel, M Laversanne, I Soerjomataram, A Jemal, F Bray. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71( 3): 209– 249 https://doi.org/10.3322/caac.21660 pmid: 33538338
3	ZH Tang, JJ Lu. Osimertinib resistance in non-small cell lung cancer: mechanisms and therapeutic strategies. Cancer Lett 2018; 420 : 242– 246 https://doi.org/10.1016/j.canlet.2018.02.004 pmid: 29425688
4	SS Ramalingam, J Vansteenkiste, D Planchard, BC Cho, JE Gray, Y Ohe, C Zhou, T Reungwetwattana, Y Cheng, B Chewaskulyong, R Shah, M Cobo, KH Lee, P Cheema, M Tiseo, T John, MC Lin, F Imamura, T Kurata, A Todd, R Hodge, M Saggese, Y Rukazenkov, JC; FLAURA Investigators Soria. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med 2020; 382( 1): 41– 50 https://doi.org/10.1056/NEJMoa1913662 pmid: 31751012
5	JC Soria, Y Ohe, J Vansteenkiste, T Reungwetwattana, B Chewaskulyong, KH Lee, A Dechaphunkul, F Imamura, N Nogami, T Kurata, I Okamoto, C Zhou, BC Cho, Y Cheng, EK Cho, PJ Voon, D Planchard, WC Su, JE Gray, SM Lee, R Hodge, M Marotti, Y Rukazenkov, SS; FLAURA Investigators Ramalingam. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018; 378( 2): 113– 125 https://doi.org/10.1056/NEJMoa1713137 pmid: 29151359
6	S Lu, Q Wang, G Zhang, X Dong, CT Yang, Y Song, GC Chang, Y Lu, H Pan, CH Chiu, Z Wang, J Feng, J Zhou, X Xu, R Guo, J Chen, H Yang, Y Chen, Z Yu, HS Shiah, CC Wang, N Yang, J Fang, P Wang, K Wang, Y Hu, J He, Z Wang, J Shi, S Chen, Q Wu, C Sun, C Li, H Wei, Y Cheng, WC Su, TC Hsia, J Cui, Y Sun, SI Ou, VW Zhu, J Chih-Hsin Yang. Efficacy of aumolertinib (HS-10296) in patients with advanced EGFR T790M+ NSCLC: updated post-national medical products administration approval results from the APOLLO registrational trial. J Thorac Oncol 2022; 17( 3): 411– 422 https://doi.org/10.1016/j.jtho.2021.10.024 pmid: 34801749
7	D Romero. Aumolertinib is effective in NSCLC. Nat Rev Clin Oncol 2022; 19( 1): 6 https://doi.org/10.1038/s41571-021-00586-x pmid: 34845385
8	S Schmid, JJN Li, NB Leighl. Mechanisms of osimertinib resistance and emerging treatment options. Lung Cancer 2020; 147 : 123– 129 https://doi.org/10.1016/j.lungcan.2020.07.014 pmid: 32693293
9	D Hanahan, RA Weinberg. Hallmarks of cancer: the next generation. Cell 2011; 144( 5): 646– 674 https://doi.org/10.1016/j.cell.2011.02.013 pmid: 21376230
10	D Hanahan. Hallmarks of cancer: new dimensions. Cancer Discov 2022; 12( 1): 31– 46 https://doi.org/10.1158/2159-8290.CD-21-1059 pmid: 35022204
11	ST Diepstraten, MA Anderson, PE Czabotar, G Lessene, A Strasser, GL Kelly. The manipulation of apoptosis for cancer therapy using BH3-mimetic drugs. Nat Rev Cancer 2022; 22( 1): 45– 64 https://doi.org/10.1038/s41568-021-00407-4 pmid: 34663943
12	KC Zimmermann, DR Green. How cells die: apoptosis pathways. J Allergy Clin Immunol 2001; 108( 4 Suppl): S99– S103 https://doi.org/10.1067/mai.2001.117819 pmid: 11586274
13	MO Hengartner. The biochemistry of apoptosis. Nature 2000; 407( 6805): 770– 776 https://doi.org/10.1038/35037710 pmid: 11048727
14	A Ashkenazi, VM Dixit. Death receptors: signaling and modulation. Science 1998; 281( 5381): 1305– 1308 https://doi.org/10.1126/science.281.5381.1305 pmid: 9721089
15	A Ashkenazi, VM Dixit. Apoptosis control by death and decoy receptors. Curr Opin Cell Biol 1999; 11( 2): 255– 260 https://doi.org/10.1016/S0955-0674(99)80034-9 pmid: 10209153
16	I Lavrik, A Golks, PH Krammer. Death receptor signaling. J Cell Sci 2005; 118( 2): 265– 267 https://doi.org/10.1242/jcs.01610 pmid: 15654015
17	A Krueger, S Baumann, PH Krammer, S Kirchhoff. FLICE-inhibitory proteins: regulators of death receptor-mediated apoptosis. Mol Cell Biol 2001; 21( 24): 8247– 8254 https://doi.org/10.1128/MCB.21.24.8247-8254.2001 pmid: 11713262
18	RC Budd, WC Yeh, J Tschopp. cFLIP regulation of lymphocyte activation and development. Nat Rev Immunol 2006; 6( 3): 196– 204 https://doi.org/10.1038/nri1787 pmid: 16498450
19	H Wajant. Targeting the FLICE Inhibitory Protein (FLIP) in cancer therapy. Mol Interv 2003; 3( 3): 124– 127 https://doi.org/10.1124/mi.3.3.124 pmid: 14993418
20	T Kataoka. The caspase-8 modulator c-FLIP. Crit Rev Immunol 2005; 25( 1): 31– 58 https://doi.org/10.1615/CritRevImmunol.v25.i1.30 pmid: 15833082
21	Y Kim, N Suh, M Sporn, JC Reed. An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis. J Biol Chem 2002; 277( 25): 22320– 22329 https://doi.org/10.1074/jbc.M202458200 pmid: 11940602
22	M Poukkula, A Kaunisto, V Hietakangas, K Denessiouk, T Katajamäki, MS Johnson, L Sistonen, JE Eriksson. Rapid turnover of c-FLIPshort is determined by its unique C-terminal tail. J Biol Chem 2005; 280( 29): 27345– 27355 https://doi.org/10.1074/jbc.M504019200 pmid: 15886205
23	L Chang, H Kamata, G Solinas, JL Luo, S Maeda, K Venuprasad, YC Liu, M Karin. The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover. Cell 2006; 124( 3): 601– 613 https://doi.org/10.1016/j.cell.2006.01.021 pmid: 16469705
24	C Falschlehner, U Schaefer, H Walczak. Following TRAIL’s path in the immune system. Immunology 2009; 127( 2): 145– 154 https://doi.org/10.1111/j.1365-2567.2009.03058.x pmid: 19476510
25	RW Johnstone, AJ Frew, MJ Smyth. The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nat Rev Cancer 2008; 8( 10): 782– 798 https://doi.org/10.1038/nrc2465 pmid: 18813321
26	Reilly E O’, A Tirincsi, SE Logue, E Szegezdi. The Janus face of death receptor signaling during tumor immunoediting. Front Immunol 2016; 7 : 446 https://doi.org/10.3389/fimmu.2016.00446 pmid: 27843441
27	WD Fairlie, EF Lee. Targeting the BCL-2-regulated apoptotic pathway for the treatment of solid cancers. Biochem Soc Trans 2021; 49( 5): 2397– 2410 https://doi.org/10.1042/BST20210750 pmid: 34581776
28	D Westaby, JM Jimenez-Vacas, A Padilha, A Varkaris, SP Balk, JS de Bono, A Sharp. Targeting the intrinsic apoptosis pathway: a window of opportunity for prostate cancer. Cancers (Basel) 2021; 14( 1): 51 https://doi.org/10.3390/cancers14010051 pmid: 35008216
29	P Shi, YT Oh, L Deng, G Zhang, G Qian, S Zhang, H Ren, G Wu, B Jr Legendre, E Anderson, SS Ramalingam, TK Owonikoko, M Chen, SY Sun. Overcoming acquired resistance to AZD9291, a third-generation EGFR inhibitor, through modulation of MEK/ERK-dependent Bim and Mcl-1 degradation. Clin Cancer Res 2017; 23( 21): 6567– 6579 https://doi.org/10.1158/1078-0432.CCR-17-1574 pmid: 28765329
30	X Ge, Y Zhang, F Huang, Y Wu, J Pang, X Li, F Fan, H Liu, S Li. EGFR tyrosine kinase inhibitor almonertinib induces apoptosis and autophagy mediated by reactive oxygen species in non-small cell lung cancer cells. Hum Exp Toxicol 2021; 40( 12_suppl): S49– S62 https://doi.org/10.1177/09603271211030554 pmid: 34219533
31	P Shi, S Zhang, L Zhu, G Qian, H Ren, SS Ramalingam, M Chen, SY Sun. The third-generation EGFR inhibitor, osimertinib, promotes c-FLIP degradation, enhancing apoptosis including TRAIL-induced apoptosis in NSCLC cells with activating EGFR mutations. Transl Oncol 2019; 12( 5): 705– 713 https://doi.org/10.1016/j.tranon.2019.02.006 pmid: 30856555
32	S Zhang, Z Chen, P Shi, S Fan, Y He, Q Wang, Y Li, SS Ramalingam, TK Owonikoko, SY Sun. Downregulation of death receptor 4 is tightly associated with positive response of EGFR mutant lung cancer to EGFR-targeted therapy and improved prognosis. Theranostics 2021; 11( 8): 3964– 3980 https://doi.org/10.7150/thno.54824 pmid: 33664875
33	A Leonetti, S Sharma, R Minari, P Perego, E Giovannetti, M Tiseo. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer 2019; 121( 9): 725– 737 https://doi.org/10.1038/s41416-019-0573-8 pmid: 31564718
34	CH Weng, LY Chen, YC Lin, JY Shih, YC Lin, RY Tseng, AC Chiu, YH Yeh, C Liu, YT Lin, JM Fang, CC Chen. Epithelial-mesenchymal transition (EMT) beyond EGFR mutations per se is a common mechanism for acquired resistance to EGFR TKI. Oncogene 2019; 38( 4): 455– 468 https://doi.org/10.1038/s41388-018-0454-2 pmid: 30111817
35	ZA Yochum, J Cades, H Wang, S Chatterjee, BW Simons, JP O’Brien, SK Khetarpal, G Lemtiri-Chlieh, KV Myers, EH Huang, CM Rudin, PT Tran, TF Burns. Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer. Oncogene 2019; 38( 5): 656– 670 https://doi.org/10.1038/s41388-018-0482-y pmid: 30171258
36	TH Chang, MF Tsai, KY Su, SG Wu, CP Huang, SL Yu, YL Yu, CC Lan, CH Yang, SB Lin, CP Wu, JY Shih, PC Yang. Slug confers resistance to the epidermal growth factor receptor tyrosine kinase inhibitor. Am J Respir Crit Care Med 2011; 183( 8): 1071– 1079 https://doi.org/10.1164/rccm.201009-1440OC pmid: 21037017
37	KA Song, MJ Niederst, TL Lochmann, AN Hata, H Kitai, J Ham, KV Floros, MA Hicks, H Hu, HE Mulvey, Y Drier, DAR Heisey, MT Hughes, NU Patel, EL Lockerman, A Garcia, S Gillepsie, HL Archibald, M Gomez-Caraballo, TJ Nulton, BE Windle, Z Piotrowska, SE Sahingur, SM Taylor, M Dozmorov, LV Sequist, B Bernstein, H Ebi, JA Engelman, AC Faber. Epithelial-to-mesenchymal transition antagonizes response to targeted therapies in lung cancer by suppressing BIM. Clin Cancer Res 2018; 24( 1): 197– 208 https://doi.org/10.1158/1078-0432.CCR-17-1577 pmid: 29051323
38	Q Qin, X Li, X Liang, L Zeng, J Wang, L Sun, D Zhong. Targeting the EMT transcription factor Snail overcomes resistance to osimertinib in EGFR-mutant non-small cell lung cancer. Thorac Cancer 2021; 12( 11): 1708– 1715 https://doi.org/10.1111/1759-7714.13906 pmid: 33943009
39	XM Jiang, YL Xu, LW Yuan, LL Zhang, MY Huang, ZH Ye, MX Su, XP Chen, H Zhu, RD Ye, JJ Lu. TGFβ2-mediated epithelial-mesenchymal transition and NF-κB pathway activation contribute to osimertinib resistance. Acta Pharmacol Sin 2021; 42( 3): 451– 459 https://doi.org/10.1038/s41401-020-0457-8 pmid: 32678313
40	AC Faber, RB Corcoran, H Ebi, LV Sequist, BA Waltman, E Chung, J Incio, SR Digumarthy, SF Pollack, Y Song, A Muzikansky, E Lifshits, S Roberge, EJ Coffman, CH Benes, HL Gómez, J Baselga, CL Arteaga, MN Rivera, D Dias-Santagata, RK Jain, JA Engelman. BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors. Cancer Discov 2011; 1( 4): 352– 365 https://doi.org/10.1158/2159-8290.CD-11-0106 pmid: 22145099
41	C Costa, MA Molina, A Drozdowskyj, A Giménez-Capitán, J Bertran-Alamillo, N Karachaliou, R Gervais, B Massuti, J Wei, T Moran, M Majem, E Felip, E Carcereny, R Garcia-Campelo, S Viteri, M Taron, M Ono, P Giannikopoulos, T Bivona, R Rosell. The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial. Clin Cancer Res 2014; 20( 7): 2001– 2010 https://doi.org/10.1158/1078-0432.CCR-13-2233 pmid: 24493829
42	KP Ng, AM Hillmer, CT Chuah, WC Juan, TK Ko, AS Teo, PN Ariyaratne, N Takahashi, K Sawada, Y Fei, S Soh, WH Lee, JW Huang, JC Jr Allen, XY Woo, N Nagarajan, V Kumar, A Thalamuthu, WT Poh, AL Ang, HT Mya, GF How, LY Yang, LP Koh, B Chowbay, CT Chang, VS Nadarajan, WJ Chng, H Than, LC Lim, YT Goh, S Zhang, D Poh, P Tan, JE Seet, MK Ang, NM Chau, QS Ng, DS Tan, M Soda, K Isobe, MM Nöthen, TY Wong, A Shahab, X Ruan, V Cacheux-Rataboul, WK Sung, EH Tan, Y Yatabe, H Mano, RA Soo, TM Chin, WT Lim, Y Ruan, ST Ong. A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nat Med 2012; 18( 4): 521– 528 https://doi.org/10.1038/nm.2713 pmid: 22426421
43	K Isobe, A Kakimoto, T Mikami, K Kaburaki, H Kobayashi, T Yoshizawa, T Makino, H Otsuka, GO Sano, K Sugino, S Sakamoto, Y Takai, N Tochigi, A Iyoda, S Homma. Association of BIM deletion polymorphism and BIM-γ RNA expression in NSCLC with EGFR mutation. Cancer Genomics Proteomics 2016; 13( 6): 475– 482 https://doi.org/10.21873/cgp.20010 pmid: 27807070
44	SG Wu, YN Liu, CJ Yu, PC Yang, JY Shih. Association of BIM deletion polymorphism with intrinsic resistance to EGFR tyrosine kinase inhibitors in patients with lung adenocarcinoma. JAMA Oncol 2016; 2( 6): 826– 828 https://doi.org/10.1001/jamaoncol.2016.0016 pmid: 27077907
45	K Isobe, Y Hata, N Tochigi, K Kaburaki, H Kobayashi, T Makino, H Otsuka, F Sato, F Ishida, N Kikuchi, N Hirota, K Sato, G Sano, K Sugino, S Sakamoto, Y Takai, K Shibuya, A Iyoda, S Homma. Clinical significance of BIM deletion polymorphism in non-small-cell lung cancer with epidermal growth factor receptor mutation. J Thorac Oncol 2014; 9( 4): 483– 487 https://doi.org/10.1097/JTO.0000000000000125 pmid: 24736070
46	JK Lee, JY Shin, S Kim, S Lee, C Park, JY Kim, Y Koh, B Keam, HS Min, TM Kim, YK Jeon, DW Kim, DH Chung, DS Heo, SH Lee, JI Kim. Primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer harboring TKI-sensitive EGFR mutations: an exploratory study. Ann Oncol 2013; 24( 8): 2080– 2087 https://doi.org/10.1093/annonc/mdt127 pmid: 23559152
47	A Tanimoto, S Takeuchi, S Arai, K Fukuda, T Yamada, X Roca, ST Ong, S Yano. Histone deacetylase 3 inhibition overcomes BIM deletion polymorphism-mediated osimertinib resistance in EGFR-mutant lung cancer. Clin Cancer Res 2017; 23( 12): 3139– 3149 https://doi.org/10.1158/1078-0432.CCR-16-2271 pmid: 27986747
48	X Li, D Zhang, B Li, B Zou, S Wang, B Fan, W Li, J Yu, L Wang. Clinical implications of germline BCL2L11 deletion polymorphism in pretreated advanced NSCLC patients with osimertinib therapy. Lung Cancer 2021; 151 : 39– 43 https://doi.org/10.1016/j.lungcan.2020.12.002 pmid: 33296806
49	K Isobe, T Yoshizawa, M Sekiya, S Miyoshi, Y Nakamura, N Urabe, T Isshiki, S Sakamoto, Y Takai, T Tomida, S Adachi-Akahane, A Iyoda, S Homma, K Kishi. Quantification of BIM mRNA in circulating tumor cells of osimertinib-treated patients with EGFR mutation-positive lung cancer. Respir Investig 2021; 59( 4): 535– 544 https://doi.org/10.1016/j.resinv.2021.03.010 pmid: 33934994
50	S Chen, L Fu, SM Raja, P Yue, FR Khuri, SY Sun. Dissecting the roles of DR4, DR5 and c-FLIP in the regulation of geranylgeranyltransferase I inhibition-mediated augmentation of TRAIL-induced apoptosis. Mol Cancer 2010; 9( 1): 23 https://doi.org/10.1186/1476-4598-9-23 pmid: 20113484
51	T Hartwig, A Montinaro, S von Karstedt, A Sevko, S Surinova, A Chakravarthy, L Taraborrelli, P Draber, E Lafont, F Arce Vargas, MA El-Bahrawy, SA Quezada, H Walczak. The TRAIL-induced cancer secretome promotes a tumor-supportive immune microenvironment via CCR2. Mol Cell 2017; 65( 4): 730– 742.e5 https://doi.org/10.1016/j.molcel.2017.01.021 pmid: 28212753
52	CM Henry, SJ Martin. Caspase-8 acts in a non-enzymatic role as a scaffold for assembly of a pro-inflammatory “FADDosome” complex upon TRAIL stimulation. Mol Cell 2017; 65( 4): 715– 729.e5 https://doi.org/10.1016/j.molcel.2017.01.022 pmid: 28212752
53	Y Li, H Zang, G Qian, TK Owonikoko, SR Ramalingam, SY Sun. ERK inhibition effectively overcomes acquired resistance of epidermal growth factor receptor-mutant non-small cell lung cancer cells to osimertinib. Cancer 2020; 126( 6): 1339– 1350 https://doi.org/10.1002/cncr.32655 pmid: 31821539
54	W Jiang, F Cai, H Xu, Y Lu, J Chen, J Liu, N Cao, X Zhang, X Chen, Q Huang, H Zhuang, ZC Hua. Extracellular signal regulated kinase 5 promotes cell migration, invasion and lung metastasis in a FAK-dependent manner. Protein Cell 2020; 11( 11): 825– 845 https://doi.org/10.1007/s13238-020-00701-1 pmid: 32144580
55	J Jiang, LG Zhao, YJ Teng, SL Chen, LP An, JL Ma, J Wang, YY Xia. ERK5 signalling pathway is essential for fluid shear stress-induced COX-2 gene expression in MC3T3-E1 osteoblast. Mol Cell Biochem 2015; 406( 1–2): 237– 243 https://doi.org/10.1007/s11010-015-2441-z pmid: 25976667
56	Z Liang, W Xie, R Wu, H Geng, L Zhao, C Xie, X Li, C Huang, J Zhu, M Zhu, W Zhu, J Wu, S Geng, C Zhong. ERK5 negatively regulates tobacco smoke-induced pulmonary epithelial-mesenchymal transition. Oncotarget 2015; 6( 23): 19605– 19618 https://doi.org/10.18632/oncotarget.3747 pmid: 25965818
57	SJ Park, YS Choi, S Lee, YJ Lee, S Hong, S Han, BC Kim. BIX02189 inhibits TGF-β1-induced lung cancer cell metastasis by directly targeting TGF-β type I receptor. Cancer Lett 2016; 381( 2): 314– 322 https://doi.org/10.1016/j.canlet.2016.08.010 pmid: 27543359
58	W Zhao, D Yu, Z Chen, W Yao, J Yang, SS Ramalingam, SY Sun. Inhibition of MEK5/ERK5 signaling overcomes acquired resistance to the third generation EGFR inhibitor, osimertinib, via enhancing Bim-dependent apoptosis. Cancer Lett 2021; 519 : 141– 149 https://doi.org/10.1016/j.canlet.2021.07.007 pmid: 34245854
59	H Zang, G Qian, D Zong, S Fan, TK Owonikoko, SS Ramalingam, SY Sun. Overcoming acquired resistance of epidermal growth factor receptor-mutant non-small cell lung cancer cells to osimertinib by combining osimertinib with the histone deacetylase inhibitor panobinostat (LBH589). Cancer 2020; 126( 9): 2024– 2033 https://doi.org/10.1002/cncr.32744 pmid: 31999837
60	F Cao, YB Gong, XH Kang, ZH Lu, Y Wang, KL Zhao, ZH Miao, MJ Liao, ZY Xu. Degradation of MCL-1 by bufalin reverses acquired resistance to osimertinib in EGFR-mutant lung cancer. Toxicol Appl Pharmacol 2019; 379 : 114662 https://doi.org/10.1016/j.taap.2019.114662 pmid: 31301315
61	H Zang, G Qian, J Arbiser, TK Owonikoko, SS Ramalingam, S Fan, SY Sun. Overcoming acquired resistance of EGFR-mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib, with the natural product honokiol. Mol Oncol 2020; 14( 4): 882– 895 https://doi.org/10.1002/1878-0261.12645 pmid: 32003107
62	Z Chen, KA Vallega, H Chen, J Zhou, SS Ramalingam, SY Sun. The natural product berberine synergizes with osimertinib preferentially against MET-amplified osimertinib-resistant lung cancer via direct MET inhibition. Pharmacol Res 2022; 175 : 105998 https://doi.org/10.1016/j.phrs.2021.105998 pmid: 34826601
63	R Han, S Hao, C Lu, C Zhang, C Lin, L Li, Y Wang, C Hu, Y He. Aspirin sensitizes osimertinib-resistant NSCLC cells in vitro and in vivo via Bim-dependent apoptosis induction. Mol Oncol 2020; 14( 6): 1152– 1169 https://doi.org/10.1002/1878-0261.12682 pmid: 32239624
64	Z Chen, D Yu, TK Owonikoko, SS Ramalingam, SY Sun. Induction of SREBP1 degradation coupled with suppression of SREBP1-mediated lipogenesis impacts the response of EGFR mutant NSCLC cells to osimertinib. Oncogene 2021; 40( 49): 6653– 6665 https://doi.org/10.1038/s41388-021-02057-0 pmid: 34635799
65	L Zhu, Z Chen, H Zang, S Fan, J Gu, G Zhang, KD Sun, Q Wang, Y He, TK Owonikoko, SS Ramalingam, SY Sun. Targeting c-Myc to overcome acquired resistance of EGFR mutant NSCLC cells to the third-generation EGFR tyrosine kinase inhibitor, osimertinib. Cancer Res 2021; 81( 18): 4822– 4834 https://doi.org/10.1158/0008-5472.CAN-21-0556 pmid: 34289988
66	K Tanaka, HA Yu, S Yang, S Han, SD Selcuklu, K Kim, S Ramani, YT Ganesan, A Moyer, S Sinha, Y Xie, K Ishizawa, HU Osmanbeyoglu, Y Lyu, N Roper, U Guha, CM Rudin, MG Kris, JJ Hsieh, EH Cheng. Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis. Cancer Cell 2021; 39( 9): 1245– 1261.e6 https://doi.org/10.1016/j.ccell.2021.07.006 pmid: 34388376
67	S Watanabe, T Yoshida, H Kawakami, N Takegawa, J Tanizaki, H Hayashi, M Takeda, K Yonesaka, J Tsurutani, K Nakagawa. T790M-selective EGFR-TKI combined with dasatinib as an optimal strategy for overcoming EGFR-TKI resistance in T790M-positive non-small cell lung cancer. Mol Cancer Ther 2017; 16( 11): 2563– 2571 https://doi.org/10.1158/1535-7163.MCT-17-0351 pmid: 28839001
68	G Ma, Y Deng, L Qian, KA Vallega, G Zhang, X Deng, TK Owonikoko, SS Ramalingam, DD Fang, Y Zhai, SY Sun. Overcoming acquired resistance to third-generation EGFR inhibitors by targeting activation of intrinsic apoptotic pathway through Mcl-1 inhibition, Bax activation, or both. Oncogene 2022; 41( 12): 1691– 1700 https://doi.org/10.1038/s41388-022-02200-5 pmid: 35102249
69	Y Lu, D Bian, X Zhang, H Zhang, Z Zhu. Inhibition of Bcl-2 and Bcl-xL overcomes the resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer. Mol Med Rep 2021; 23( 1): 48 https://doi.org/10.3892/mmr.2020.11686 pmid: 33200796
70	Z Liu, W Gao. Synergistic effects of Bcl-2 inhibitors with AZD9291 on overcoming the acquired resistance of AZD9291 in H1975 cells. Arch Toxicol 2020; 94( 9): 3125– 3136 https://doi.org/10.1007/s00204-020-02816-0 pmid: 32577785
71	K Suda, T Mitsudomi. Drug tolerance to EGFR tyrosine kinase inhibitors in lung cancers with EGFR mutations. Cells 2021; 10( 7): 1590 https://doi.org/10.3390/cells10071590 pmid: 34202566
72	HF Cabanos, AN Hata. Emerging insights into targeted therapy-tolerant persister cells in cancer. Cancers (Basel) 2021; 13( 11): 2666 https://doi.org/10.3390/cancers13112666 pmid: 34071428
73	SV Sharma, DY Lee, B Li, MP Quinlan, F Takahashi, S Maheswaran, U McDermott, N Azizian, L Zou, MA Fischbach, KK Wong, K Brandstetter, B Wittner, S Ramaswamy, M Classon, J Settleman. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 2010; 141( 1): 69– 80 https://doi.org/10.1016/j.cell.2010.02.027 pmid: 20371346
74	AN Hata, MJ Niederst, HL Archibald, M Gomez-Caraballo, FM Siddiqui, HE Mulvey, YE Maruvka, F Ji, HE Bhang, V Krishnamurthy Radhakrishna, G Siravegna, H Hu, S Raoof, E Lockerman, A Kalsy, D Lee, CL Keating, DA Ruddy, LJ Damon, AS Crystal, C Costa, Z Piotrowska, A Bardelli, AJ Iafrate, RI Sadreyev, F Stegmeier, G Getz, LV Sequist, AC Faber, JA Engelman. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med 2016; 22( 3): 262– 269 https://doi.org/10.1038/nm.4040 pmid: 26828195
75	KJ Kurppa, Y Liu, C To, T Zhang, M Fan, A Vajdi, EH Knelson, Y Xie, K Lim, P Cejas, A Portell, PH Lizotte, SB Ficarro, S Li, T Chen, HM Haikala, H Wang, M Bahcall, Y Gao, S Shalhout, S Boettcher, BH Shin, T Thai, MK Wilkens, ML Tillgren, M Mushajiang, M Xu, J Choi, AA Bertram, BL Ebert, R Beroukhim, P Bandopadhayay, MM Awad, PC Gokhale, PT Kirschmeier, JA Marto, FD Camargo, R Haq, CP Paweletz, KK Wong, DA Barbie, HW Long, NS Gray, PA Jänne. Treatment-induced tumor dormancy through YAP-mediated transcriptional reprogramming of the apoptotic pathway. Cancer Cell 2020; 37( 1): 104– 122.e12 https://doi.org/10.1016/j.ccell.2019.12.006 pmid: 31935369
76	J Gu, W Yang, P Shi, G Zhang, TK Owonikoko, SR Ramalingam, SY Sun. MEK or ERK inhibition effectively abrogates emergence of acquired osimertinib resistance in the treatment of epidermal growth factor receptor-mutant lung cancers. Cancer 2020; 126 : 3788– 3799 https://doi.org/10.1002/cncr.32996 pmid: 32497272
77	TG Cotter. Apoptosis and cancer: the genesis of a research field. Nat Rev Cancer 2009; 9( 7): 501– 507 https://doi.org/10.1038/nrc2663 pmid: 19550425
78	SW Fesik. Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer 2005; 5( 11): 876– 885 https://doi.org/10.1038/nrc1736 pmid: 16239906

[1]	Xiang Wang, Minghui Wang, Lin Feng, Jie Song, Xin Dong, Ting Xiao, Shujun Cheng. Four-protein model for predicting prognostic risk of lung cancer[J]. Front. Med., 2022, 16(4): 618-626.
[2]	Yaru Tian, Hairong Tian, Xiaoyang Zhai, Hui Zhu, Jinming Yu. Bevacizumab in combination with pemetrexed and platinum for elderly patients with advanced non-squamous non-small-cell lung cancer: a retrospective analysis[J]. Front. Med., 2022, 16(4): 610-617.
[3]	Wenjing Zhou, Jing Zhang, Mingkun Yan, Jin Wu, Shuo Lian, Kang Sun, Baiqing Li, Jia Ma, Jun Xia, Chaoqun Lian. Orlistat induces ferroptosis-like cell death of lung cancer cells[J]. Front. Med., 2021, 15(6): 922-932.
[4]	Na Qin, Yuancheng Li, Cheng Wang, Meng Zhu, Juncheng Dai, Tongtong Hong, Demetrius Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Gary Goodman, Stig E. Bojesen, Maria Teresa Landi, Mattias Johansson, Angela Risch, H-Erich Wichmann, Heike Bickeboller, Gadi Rennert, Susanne Arnold, Paul Brennan, John K. Field, Sanjay Shete, Loic Le Marchand, Olle Melander, Hans Brunnstrom, Geoffrey Liu, Rayjean J. Hung, Angeline Andrew, Lambertus A. Kiemeney, Shan Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil Caporaso, Penella Woll, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Victoria L. Stevens, Guangfu Jin, David C. Christiani, Zhibin Hu, Christopher I. Amos, Hongxia Ma, Hongbing Shen. Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma[J]. Front. Med., 2021, 15(2): 275-291.
[5]	Jiahui Xu, Qianqian Wang, Elaine Lai Han Leung, Ying Li, Xingxing Fan, Qibiao Wu, Xiaojun Yao, Liang Liu. Compound C620-0696, a new potent inhibitor targeting BPTF, the chromatin-remodeling factor in non-small-cell lung cancer[J]. Front. Med., 2020, 14(1): 60-67.
[6]	Zhao Zhang, Jun Jiang, Xiaodong Wu, Mengyao Zhang, Dan Luo, Renyu Zhang, Shiyou Li, Youwen He, Huijie Bian, Zhinan Chen. Chimeric antigen receptor T cell targeting EGFRvIII for metastatic lung cancer therapy[J]. Front. Med., 2019, 13(1): 57-68.
[7]	Kohei Miyazono, Yoko Katsuno, Daizo Koinuma, Shogo Ehata, Masato Morikawa. Intracellular and extracellular TGF-β signaling in cancer: some recent topics[J]. Front. Med., 2018, 12(4): 387-411.
[8]	Dalin Zhang, Liwei Qu, Bo Zhou, Guizhen Wang, Guangbiao Zhou. Genomic variations in the counterpart normal controls of lung squamous cell carcinomas[J]. Front. Med., 2018, 12(3): 280-288.
[9]	Hongbing Shen. Low-dose CT for lung cancer screening: opportunities and challenges[J]. Front. Med., 2018, 12(1): 116-121.
[10]	Qiuxia Han, Hanyu Zhu, Xiangmei Chen, Zhangsuo Liu. Non-genetic mechanisms of diabetic nephropathy[J]. Front. Med., 2017, 11(3): 319-332.
[11]	Alexandra Urman,H. Dean Hosgood. Curbing the burden of lung cancer[J]. Front. Med., 2016, 10(2): 228-232.
[12]	Li Bian,Yonghua Ruan,Liju Ma,Hairong Hua,Li Zhou,Xiaoyu Tuo,Zheyan Zhou,Ting Li,Shiyue Liu,Kewei Jin. Pathogenesis sequences in Gejiu miners with lung cancer: an introduction[J]. Front. Med., 2015, 9(3): 344-349.
[13]	Douglas D. Fang, Joan Cao, Jitesh P. Jani, Konstantinos Tsaparikos, Alessandra Blasina, Jill Kornmann, Maruja E. Lira, Jianying Wang, Zuzana Jirout, Justin Bingham, Zhou Zhu, Yin Gu, Gerrit Los, Zdenek Hostomsky, Todd VanArsdale. Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like cells enriched with tumor spheroids from a non-small cell lung cancer cell line[J]. Front Med, 2013, 7(4): 462-476.
[14]	Min ZHU, Xiang-Ning FU, Xiao-Ping CHEN. Lobectomy by video-assisted thoracoscopic surgery (VATS) for early stage of non-small cell lung cancer[J]. Front Med, 2011, 5(1): 53-60.
[15]	Dian-Ke YU PhD, Chen WU MD, Wen TAN MD, Dong-Xin LIN MD, . Functional XPF polymorphisms associated with lung cancer susceptibility in a Chinese population[J]. Front. Med., 2010, 4(1): 82-89.

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