REFERENCES
1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229-63.
2. Metwally EM, Rivera MP, Durham DD, et al. Lung cancer screening in individuals with and without lung-related comorbidities. JAMA Netw Open. 2022;5:e2230146.
3. Garg P, Singhal S, Kulkarni P, et al. Advances in non-small cell lung cancer: current insights and future directions. J Clin Med. 2024;13:4189.
4. Ganti AK, Klein AB, Cotarla I, Seal B, Chou E. Update of incidence, prevalence, survival, and initial treatment in patients with non-small cell lung cancer in the US. JAMA Oncol. 2021;7:1824-32.
5. He S, Li H, Cao M, et al. Survival of 7,311 lung cancer patients by pathological stage and histological classification: a multicenter hospital-based study in China. Transl Lung Cancer Res. 2022;11:1591-605.
6. Calvo V, Aliaga C, Carracedo C, Provencio M. Prognostic factors in potentially resectable stage III non-small cell lung cancer receiving neoadjuvant treatment-a narrative review. Transl Lung Cancer Res. 2021;10:581-9.
7. Alexander M, Kim SY, Cheng H. Update 2020: management of non-small cell lung cancer. Lung. 2020;198:897-907.
8. Wang M, Herbst RS, Boshoff C. Toward personalized treatment approaches for non-small-cell lung cancer. Nat Med. 2021;27:1345-56.
9. Hirsch FR, Scagliotti GV, Mulshine JL, et al. Lung cancer: current therapies and new targeted treatments. Lancet. 2017;389:299-311.
10. Chang JY, Mehran RJ, Feng L, et al. Stereotactic ablative radiotherapy for operable stage I non-small-cell lung cancer (revised STARS): long-term results of a single-arm, prospective trial with prespecified comparison to surgery. Lancet Oncol. 2021;22:1448-57.
11. Chang JY, Lin SH, Dong W, et al. Stereotactic ablative radiotherapy with or without immunotherapy for early-stage or isolated lung parenchymal recurrent node-negative non-small-cell lung cancer: an open-label, randomised, phase 2 trial. Lancet. 2023;402:871-81.
12. Lee JM, McNamee CJ, Toloza E, et al. Neoadjuvant targeted therapy in resectable NSCLC: current and future perspectives. J Thorac Oncol. 2023;18:1458-77.
13. Zhou Y, Li A, Yu H, et al. Neoadjuvant-adjuvant vs neoadjuvant-only PD-1 and PD-L1 Inhibitors for patients with resectable NSCLC: an indirect meta-analysis. JAMA Netw Open. 2024;7:e241285.
14. Sorin M, Prosty C, Ghaleb L, et al. Neoadjuvant chemoimmunotherapy for NSCLC: a systematic review and meta-analysis. JAMA Oncol. 2024;10:621-33.
15. Imyanitov EN, Iyevleva AG, Levchenko EV. Molecular testing and targeted therapy for non-small cell lung cancer: current status and perspectives. Crit Rev Oncol Hematol. 2021;157:103194.
16. Herrera-Juárez M, Serrano-Gómez C, Bote-de-Cabo H, Paz-Ares L. Targeted therapy for lung cancer: beyond EGFR and ALK. Cancer. 2023;129:1803-20.
17. Wiley SR, Schooley K, Smolak PJ, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity. 1995;3:673-82.
18. Aggarwal BB, Gupta SC, Kim JH. Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood. 2012;119:651-65.
19. Snajdauf M, Havlova K, Vachtenheim J Jr, et al. The TRAIL in the treatment of human cancer: an update on clinical trials. Front Mol Biosci. 2021;8:628332.
20. Montinaro A, Walczak H. Harnessing TRAIL-induced cell death for cancer therapy: a long walk with thrilling discoveries. Cell Death Differ. 2023;30:237-49.
21. Walczak H, Miller RE, Ariail K, et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med. 1999;5:157-63.
22. Wong SHM, Kong WY, Fang CM, et al. The TRAIL to cancer therapy: hindrances and potential solutions. Crit Rev Oncol Hematol. 2019;143:81-94.
23. von Karstedt S, Montinaro A, Walczak H. Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat Rev Cancer. 2017;17:352-66.
24. Cardoso Alves L, Corazza N, Micheau O, Krebs P. The multifaceted role of TRAIL signaling in cancer and immunity. FEBS J. 2021;288:5530-54.
25. De Wilt L, Sobocki BK, Jansen G, et al. Mechanisms underlying reversed TRAIL sensitivity in acquired bortezomib-resistant non-small cell lung cancer cells. Cancer Drug Resist. 2024;7:12.
26. Duiker EW, Mom CH, de Jong S, et al. The clinical trail of TRAIL. Eur J Cancer. 2006;42:2233-40.
28. Stegehuis JH, de Wilt LH, de Vries EG, Groen HJ, de Jong S, Kruyt FA. TRAIL receptor targeting therapies for non-small cell lung cancer: current status and perspectives. Drug Resist Updat. 2010;13:2-15.
29. van Dijk M, Halpin-McCormick A, Sessler T, Samali A, Szegezdi E. Resistance to TRAIL in non-transformed cells is due to multiple redundant pathways. Cell Death Dis. 2013;4:e702.
30. Aydin C, Sanlioglu AD, Karacay B, et al. Decoy receptor-2 small interfering RNA (siRNA) strategy employing three different siRNA constructs in combination defeats adenovirus-transferred tumor necrosis factor-related apoptosis-inducing ligand resistance in lung cancer cells. Hum Gene Ther. 2007;18:39-50.
31. Zanca C, Garofalo M, Quintavalle C, et al. PED is overexpressed and mediates TRAIL resistance in human non-small cell lung cancer. J Cell Mol Med. 2008;12:2416-26.
32. Quiroz-Reyes AG, Delgado-Gonzalez P, Islas JF, Gallegos JLD, Martínez Garza JH, Garza-Treviño EN. Behind the adaptive and resistance mechanisms of cancer stem cells to TRAIL. Pharmaceutics. 2021;13:1062.
33. Liu X, Yue P, Schönthal AH, Khuri FR, Sun SY. Cellular FLICE-inhibitory protein down-regulation contributes to celecoxib-induced apoptosis in human lung cancer cells. Cancer Res. 2006;66:11115-9.
34. Huang Y, Yang X, Xu T, et al. Overcoming resistance to TRAIL-induced apoptosis in solid tumor cells by simultaneously targeting death receptors, c-FLIP and IAPs. Int J Oncol. 2016;49:153-63.
36. Garofalo M, Quintavalle C, Di Leva G, et al. MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer. Oncogene. 2008;27:3845-55.
37. Abou El Hassan MA, Quintavalle C, Mastenbroek DC, Gerritsen WR, Giaccone G, Kruyt FA. Overexpression of Bcl2 abrogates chemo- and radiotherapy-induced sensitisation of NCI-H460 non-small-cell lung cancer cells to adenovirus-mediated expression of full-length TRAIL. Br J Cancer. 2004;91:171-7.
38. Sun SY, Yue P, Zhou JY, et al. Overexpression of BCL2 blocks TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human lung cancer cells. Biochem Biophys Res Commun. 2001;280:788-97.
39. Tian X, Srinivasan PR, Tajiknia V, et al. Targeting apoptotic pathways for cancer therapy. J Clin Invest. 2024:134.
40. Letai A. Pharmacological manipulation of Bcl-2 family members to control cell death. J Clin Invest. 2005;115:2648-55.
41. Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 2008;9:47-59.
42. Qian S, Wei Z, Yang W, Huang J, Yang Y, Wang J. The role of BCL-2 family proteins in regulating apoptosis and cancer therapy. Front Oncol. 2022;12:985363.
43. Gonzalvez F, Pariselli F, Jalmar O, et al. Mechanistic issues of the interaction of the hairpin-forming domain of tBid with mitochondrial cardiolipin. PLoS One. 2010;5:e9342.
44. Lalier L, Vallette F, Manon S. Bcl-2 family members and the mitochondrial import machineries: the roads to death. Biomolecules. 2022;12:162.
45. García-Sáez AJ, Ries J, Orzáez M, Pérez-Payà E, Schwille P. Membrane promotes tBID interaction with BCLXL. Nat Struct Mol Biol. 2009;16:1178-85.
46. Clohessy JG, Zhuang J, de Boer J, Gil-Gómez G, Brady HJ. Mcl-1 interacts with truncated Bid and inhibits its induction of cytochrome c release and its role in receptor-mediated apoptosis. J Biol Chem. 2006;281:5750-9.
47. Makinwa Y, Luo Y, Musich PR, Zou Y. Canonical and noncanonical functions of the BH3 domain protein bid in apoptosis, oncogenesis, cancer therapeutics, and aging. Cancers. 2024;16:2199.
48. Oltersdorf T, Elmore SW, Shoemaker AR, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005;435:677-81.
49. Ashkenazi A, Fairbrother WJ, Leverson JD, Souers AJ. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov. 2017;16:273-84.
50. Tantawy SI, Timofeeva N, Sarkar A, Gandhi V. Targeting MCL-1 protein to treat cancer: opportunities and challenges. Front Oncol. 2023;13:1226289.
51. Pemmaraju N, Garcia JS, Perkins A, et al. New era for myelofibrosis treatment with novel agents beyond Janus kinase-inhibitor monotherapy: focus on clinical development of BCL-XL/BCL-2 inhibition with navitoclax. Cancer. 2023;129:3535-45.
52. Konopleva M, Contractor R, Tsao T, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006;10:375-88.
53. Lin X, Morgan-Lappe S, Huang X, et al. 'Seed' analysis of off-target siRNAs reveals an essential role of Mcl-1 in resistance to the small-molecule Bcl-2/Bcl-XL inhibitor ABT-737. Oncogene. 2007;26:3972-9.
54. van Delft MF, Wei AH, Mason KD, et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell. 2006;10:389-99.
55. Wang H, Guo M, Wei H, Chen Y. Targeting MCL-1 in cancer: current status and perspectives. J Hematol Oncol. 2021;14:67.
56. Nguyen M, Marcellus RC, Roulston A, et al. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci USA. 2007;104:19512-7.
57. Or CR, Huang CW, Chang CC, Lai YC, Chen YJ, Chang CC. Obatoclax, a Pan-BCL-2 inhibitor, downregulates survivin to induce apoptosis in human colorectal carcinoma cells via suppressing WNT/β-catenin signaling. Int J Mol Sci. 2020;21:1773.
58. Chiappori A, Williams C, Northfelt DW, et al. Obatoclax mesylate, a pan-bcl-2 inhibitor, in combination with docetaxel in a phase 1/2 trial in relapsed non-small-cell lung cancer. J Thorac Oncol. 2014;9:121-5.
59. Paik PK, Rudin CM, Pietanza MC, et al. A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer. Lung Cancer. 2011;74:481-5.
60. Langer CJ, Albert I, Ross HJ, et al. Randomized phase II study of carboplatin and etoposide with or without obatoclax mesylate in extensive-stage small cell lung cancer. Lung Cancer. 2014;85:420-8.
61. Pore MM, Hiltermann TJ, Kruyt FA. Targeting apoptosis pathways in lung cancer. Cancer Lett. 2013;332:359-68.
62. Karczmarek-Borowska B, Filip A, Wojcierowski J, et al. Estimation of prognostic value of Bcl-xL gene expression in non-small cell lung cancer. Lung Cancer. 2006;51:61-9.
63. Martin B, Paesmans M, Berghmans T, et al. Role of Bcl-2 as a prognostic factor for survival in lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer. 2003;89:55-64.
64. Wesarg E, Hoffarth S, Wiewrodt R, et al. Targeting BCL-2 family proteins to overcome drug resistance in non-small cell lung cancer. Int J Cancer. 2007;121:2387-94.
65. Allen TD, Zhu CQ, Jones KD, Yanagawa N, Tsao MS, Bishop JM. Interaction between MYC and MCL1 in the genesis and outcome of non-small-cell lung cancer. Cancer Res. 2011;71:2212-21.
66. Wen Q, Zhan Y, Zheng H, et al. Elevated expression of mcl-1 inhibits apoptosis and predicts poor prognosis in patients with surgically resected non-small cell lung cancer. Diagn Pathol. 2019;14:108.
67. Anagnostou VK, Lowery FJ, Zolota V, et al. High expression of BCL-2 predicts favorable outcome in non-small cell lung cancer patients with non squamous histology. BMC Cancer. 2010;10:186.
68. Grimminger PP, Schneider PM, Metzger R, et al. The prognostic role of Bcl-2 mRNA expression in curatively resected non-small cell lung cancer (NSCLC). Lung Cancer. 2010;70:82-7.
69. Alam M, Alam S, Shamsi A, et al. Bax/Bcl-2 cascade is regulated by the EGFR pathway: therapeutic targeting of non-small cell lung cancer. Front Oncol. 2022;12:869672.
70. Honma N, HorII R, Ito Y, et al. Differences in clinical importance of Bcl-2 in breast cancer according to hormone receptors status or adjuvant endocrine therapy. BMC Cancer. 2015;15:698.
71. Luanpitpong S, Janan M, Yosudjai J, Poohadsuan J, Chanvorachote P, Issaragrisil S. Bcl-2 family members Bcl-xL and bax cooperatively contribute to bortezomib resistance in mantle cell lymphoma. Int J Mol Sci. 2022;23:14474.
72. Deng H, Lin X, Xie X, et al. Immune checkpoint inhibitors plus single-agent chemotherapy for advanced non-small-cell lung cancer after resistance to EGFR-TKI. Front Oncol. 2021;11:700023.
73. Zhong H, Zhang X, Tian P, et al. Tislelizumab plus chemotherapy for patients with EGFR-mutated non-squamous non-small cell lung cancer who progressed on EGFR tyrosine kinase inhibitor therapy. J Immunother Cancer. 2023;11:e006887.
74. Yamaguchi T, Shimizu J, Matsuzawa R, Watanabe N, Horio Y, Fujiwara Y. Efficacy of chemotherapy plus immune checkpoint inhibitors in patients with non-small cell lung cancer who have rare oncogenic driver mutations: a retrospective analysis. BMC Cancer. 2024;24:842.
75. Li H, Zhou T, Zhang Y, Jiang H, Zhang J, Hua Z. RuvBL1 maintains resistance to TRAIL-induced apoptosis by suppressing c-Jun/AP-1 activity in non-small cell lung cancer. Front Oncol. 2021;11:679243.
76. Tuomela K, Ambrose AR, Davis DM. Escaping death: how cancer cells and infected cells resist cell-mediated cytotoxicity. Front Immunol. 2022;13:867098.
77. de Wilt LH, Jansen G, Assaraf YG, et al. Proteasome-based mechanisms of intrinsic and acquired bortezomib resistance in non-small cell lung cancer. Biochem Pharmacol. 2012;83:207-17.
78. Ashkenazi A, Pai RC, Fong S, et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest. 1999;104:155-62.
79. Keepers YP, Pizao PE, Peters GJ, van Ark-Otte J, Winograd B, Pinedo HM. Comparison of the sulforhodamine B protein and tetrazolium (MTT) assays for in vitro chemosensitivity testing. Eur J Cancer. 1991;27:897-900.
80. Alley MC, Scudiero DA, Monks A, et al. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res. 1988;48:589-601.
81. Pizao PE, Lyaruu DM, Peters GJ, et al. Growth, morphology and chemosensitivity studies on postconfluent cells cultured in 'V'-bottomed microtiter plates. Br J Cancer. 1992;66:660-5.
82. Bijnsdorp IV, Kruyt FA, Gokoel S, Fukushima M, Peters GJ. Synergistic interaction between trifluorothymidine and docetaxel is sequence dependent. Cancer Sci. 2008;99:2302-8.
83. Rovithi M, Avan A, Funel N, et al. Development of bioluminescent chick chorioallantoic membrane (CAM) models for primary pancreatic cancer cells: a platform for drug testing. Sci Rep. 2017;7:44686.
84. Mapanao AK, Che PP, Sarogni P, Sminia P, Giovannetti E, Voliani V. Tumor grafted - chick chorioallantoic membrane as an alternative model for biological cancer research and conventional/nanomaterial-based theranostics evaluation. Expert Opin Drug Metab Toxicol. 2021;17:947-68.
85. Li J, Brachtlova T, van der Meulen-Muileman IH, et al. Human non-small cell lung cancer-chicken embryo chorioallantoic membrane tumor models for experimental cancer treatments. Int J Mol Sci. 2023;24:15425.
86. Kohli M, Yu J, Seaman C, et al. SMAC/Diablo-dependent apoptosis induced by nonsteroidal antIInflammatory drugs (NSAIDs) in colon cancer cells. Proc Natl Acad Sci USA. 2004;101:16897-902.
87. Hougardy BM, Maduro JH, van der Zee AG, et al. Proteasome inhibitor MG132 sensitizes HPV-positive human cervical cancer cells to rhTRAIL-induced apoptosis. Int J Cancer. 2006;118:1892-900.
88. Cillessen SA, Meijer CJ, Ossenkoppele GJ, et al. Human soluble TRAIL/Apo2L induces apoptosis in a subpopulation of chemotherapy refractory nodal diffuse large B-cell lymphomas, determined by a highly sensitive in vitro apoptosis assay. Br J Haematol. 2006;134:283-93.
89. Kahana S, Finniss S, Cazacu S, et al. Proteasome inhibitors sensitize glioma cells and glioma stem cells to TRAIL-induced apoptosis by PKCε-dependent downregulation of AKT and XIAP expressions. Cell Signal. 2011;23:1348-57.
90. Mohr A, Albarenque SM, Deedigan L, et al. Targeting of XIAP combined with systemic mesenchymal stem cell-mediated delivery of sTRAIL ligand inhibits metastatic growth of pancreatic carcinoma cells. Stem Cells. 2010;28:2109-20.
91. Rambow AC, Aschenbach I, Hagelund S, et al. Endogenous TRAIL-R4 critically impacts apoptotic and non-apoptotic TRAIL-induced signaling in cancer cells. Front Cell Dev Biol. 2022;10:942718.
92. Huang S, Okumura K, Sinicrope FA. BH3 mimetic obatoclax enhances TRAIL-mediated apoptosis in human pancreatic cancer cells. Clin Cancer Res. 2009;15:150-9.
93. Martínez-Paniagua MA, Baritaki S, Huerta-Yepez S, et al. Mcl-1 and YY1 inhibition and induction of DR5 by the BH3-mimetic Obatoclax (GX15-070) contribute in the sensitization of B-NHL cells to TRAIL apoptosis. Cell Cycle. 2011;10:2792-805.
94. Mott JL, Bronk SF, Mesa RA, Kaufmann SH, Gores GJ. BH3-only protein mimetic obatoclax sensitizes cholangiocarcinoma cells to Apo2L/TRAIL-induced apoptosis. Mol Cancer Ther. 2008;7:2339-47.
95. Song JH, Kandasamy K, Kraft AS. ABT-737 induces expression of the death receptor 5 and sensitizes human cancer cells to TRAIL-induced apoptosis. J Biol Chem. 2008;283:25003-13.
96. Khalsa JK, Cha J, Utro F, et al. Genetic events associated with venetoclax resistance in CLL identified by whole-exome sequencing of patient samples. Blood. 2023;142:421-33.
97. Diaz Rohena D, Ravikrishnan J, Liu C, et al. Targeting venetoclax-resistant CLL by Bcl-XL degradation. Blood. 2021;138:2252.
98. Diaz Rohena D, Slawin B, Ravikrishnan J, et al. Targeting venetoclax resistant CLL using a protac-based BCL-2/BCL-XL degrader. Blood. 2022;140:497-8.
99. Li X, Li B, Ni Z, et al. Metformin synergizes with BCL-XL/BCL-2 inhibitor ABT-263 to induce apoptosis specifically in p53-defective cancer cells. Mol Cancer Ther. 2017;16:1806-18.
100. Vogler M, Walczak H, Stadel D, et al. Targeting XIAP bypasses Bcl-2-mediated resistance to TRAIL and cooperates with TRAIL to suppress pancreatic cancer growth in vitro and in vivo. Cancer Res. 2008;68:7956-65.
101. Wang E, Pineda JMB, Kim WJ, et al. Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia. Cancer Cell. 2023;41:164-80.e8.
102. Reis-Silva CSM, Branco PC, Lima K, et al. Embelin potentiates venetoclax-induced apoptosis in acute myeloid leukemia cells. Toxicol In Vitro. 2021;76:105207.
103. Vogler M, Weber K, Dinsdale D, et al. Different forms of cell death induced by putative BCL2 inhibitors. Cell Death Differ. 2009;16:1030-9.
104. Brem EA, Thudium K, Khubchandani S, et al. Distinct cellular and therapeutic effects of obatoclax in rituximab-sensitive and -resistant lymphomas. Br J Haematol. 2011;153:599-611.
105. Urtishak KA, Edwards AY, Wang LS, et al. Potent obatoclax cytotoxicity and activation of triple death mode killing across infant acute lymphoblastic leukemia. Blood. 2013;121:2689-703.
106. Chen KF, Su JC, Liu CY, et al. A novel obatoclax derivative, SC-2001, induces apoptosis in hepatocellular carcinoma cells through SHP-1-dependent STAT3 inactivation. Cancer Lett. 2012;321:27-35.
107. Parrondo RD, Paulus A, Ailawadhi S. Updates in the use of BCL-2-family small molecule inhibitors for the treatment of relapsed/refractory multiple myeloma. Cancers. 2022;14:3330.
108. Czabotar PE, Garcia-Saez AJ. Mechanisms of BCL-2 family proteins in mitochondrial apoptosis. Nat Rev Mol Cell Biol. 2023;24:732-48.
109. Schimmer AD, Raza A, Carter TH, et al. A multicenter phase I/II study of obatoclax mesylate administered as a 3- or 24-hour infusion in older patients with previously untreated acute myeloid leukemia. PLoS One. 2014;9:e108694.
110. UNITED STATES SECURITIES AND EXCHANGE COMMISSION; 2012. Available from: https://www.annualreports.com/HostedData/AnnualReportArchive/t/NASDAQ_TEVA_2012.pdf [Last accessed on 26 Jun 2025].
