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Overcoming acquired resistance to third-generation EGFR inhibitors by targeting activation of intrinsic apoptotic pathway through Mcl-1 inhibition, Bax activation, or both

Oncogene volume 41, pages 1691–1700 (2022)Cite this article

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Abstract

Treatment of EGFR-mutant non-small cell lung cancer (NSCLC) with mutation-selective third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib has achieved remarkable success in the clinic. However, the immediate challenge is the emergence of acquired resistance, limiting the long-term remission of patients. This study suggests a novel strategy to overcome acquired resistance to osimertinib and other third-generation EGFR-TKIs through directly targeting the intrinsic apoptotic pathway. We found that osimertinib, when combined with Mcl-1 inhibition or Bax activation, synergistically decreased the survival of different osimertinib-resistant cell lines, enhanced the induction of intrinsic apoptosis, and inhibited the growth of osimertinib-resistant tumor in vivo. Interestingly, the triple-combination of osimertinib with Mcl-1 inhibition and Bax activation exhibited the most potent activity in decreasing the survival and inducing apoptosis of osimertinib-resistant cells and in suppressing the growth of osimertinib-resistant tumors. These effects were associated with increased activation of the intrinsic apoptotic pathway evidenced by augmented mitochondrial cytochrome C and Smac release. Hence, this study convincingly demonstrates a novel strategy for overcoming acquired resistance to osimertinib and other 3rd generation EGFR-TKIs by targeting activation of the intrinsic apoptotic pathway through Mcl-1 inhibition, Bax activation or both, warranting further clinical validation of this strategy.

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Fig. 1: The combination of osimertinib with an Mcl-1 inhibitor synergistically decreases the survival of osimertinib-resistant cell lines, which are resistant to Mcl-1 modulation by osimertinib.
Fig. 2: The combination of osimertinib with an Mcl-1 inhibitor augments the induction of apoptosis with enhanced mitochondrial release of Cyt C and Smac.
Fig. 3: The combination of osimertinib with a Bax activator synergistically decreases the survival of osimertinib-resistant cell lines.
Fig. 4: The combination of osimetrtinib with a Bax activator enhances induction of apoptosis, mitochondrial release of Cyt C and Smac and Bax oligomerization.
Fig. 5: The three-drug combination of osimertinib, CYD-2-11 and an Mcl-1 inhibitor is lethal to osimertinib-resistant EGFRm NSCLC cell lines, but not to NSCLC cell lines with wild-type EGFR.
Fig. 6: The three-drug combination of osimertinib, CYD-2-11 and an Mcl-1 inhibitor is more effective than either two-drug combination in inducing apoptosis including mitochondrial release of Cyt C and Smac in osimertinib-resistant NSCLC cells.
Fig. 7: The combination of osimertinib with an Mcl-1 inhibitor, a Bax activator, or particularly with both, exerts enhanced effects against the growth of osimertinib-resistant xenografts in nude mice and on induction of apoptosis without enhancing toxicity.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

  2. Shah R, Lester JF. Tyrosine kinase inhibitors for the treatment of EGFR mutation-positive non-small-cell lung cancer: a clash of the generations. Clin Lung Cancer. 2020;21:e216–e228.

    Article  CAS  Google Scholar 

  3. Carlisle JW, Ramalingam SS. Role of osimertinib in the treatment of EGFR-mutation positive non-small-cell lung cancer. Future Oncol. 2019;15:805–16.

    Article  CAS  Google Scholar 

  4. Piper-Vallillo AJ, Sequist LV, Piotrowska Z. Emerging treatment paradigms for EGFR-mutant lung cancers progressing on osimertinib: a review. J Clin Oncol. 2020;38:2926–36.

  5. Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382:41–50.

    Article  CAS  Google Scholar 

  6. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2017;378:113–25.

  7. Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019;121:725–37.

    Article  Google Scholar 

  8. Negi A, Murphy PV. Development of Mcl-1 inhibitors for cancer therapy. Eur J medicinal Chem. 2021;210:113038.

    Article  CAS  Google Scholar 

  9. Wang H, Guo M, Wei H, Chen Y. Targeting MCL-1 in cancer: current status and perspectives. J Hematol Oncol. 2021;14:67.

    Article  CAS  Google Scholar 

  10. Shi P, Oh YT, Deng L, Zhang G, Qian G, Zhang S, et al. 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;23:6567–79.

    Article  CAS  Google Scholar 

  11. Walensky LD. Targeting BAX to drug death directly. Nat Chem Biol. 2019;15:657–65.

    Article  CAS  Google Scholar 

  12. Pogmore JP, Uehling D, Andrews DW. Pharmacological targeting of executioner proteins: controlling life and death. J Med Chem. 2021;64:5276–90.

    Article  CAS  Google Scholar 

  13. Xin M, Li R, Xie M, Park D, Owonikoko TK, Sica GL, et al. Small-molecule Bax agonists for cancer therapy. Nat Commun. 2014;5:4935.

    Article  CAS  Google Scholar 

  14. Li R, Ding C, Zhang J, Xie M, Park D, Ding Y, et al. Modulation of Bax and mTOR for cancer therapeutics. Cancer Res. 2017;77:3001–12.

    Article  CAS  Google Scholar 

  15. Zang H, Qian G, Zong D, Fan S, Owonikoko TK, Ramalingam SS, et al. 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;126:2024–33.

    Article  CAS  Google Scholar 

  16. Cotter TG. Apoptosis and cancer: the genesis of a research field. Nat Rev Cancer. 2009;9:501–7.

    Article  CAS  Google Scholar 

  17. Fesik SW. Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer. 2005;5:876–85.

    Article  CAS  Google Scholar 

  18. Zimmermann KC, Green DR. How cells die: apoptosis pathways. J Allergy Clin Immunol. 2001;108:S99–103.

    Article  CAS  Google Scholar 

  19. Fulda S. Apoptosis pathways and their therapeutic exploitation in pancreatic cancer. J Cell Mol Med. 2009;13:1221–7.

    Article  Google Scholar 

  20. Penn LZ. Apoptosis modulators as cancer therapeutics. Curr Opin Investig Drugs. 2001;2:684–92.

    CAS  PubMed  Google Scholar 

  21. Rowinsky EK. Targeted induction of apoptosis in cancer management: the emerging role of tumor necrosis factor-related apoptosis-inducing ligand receptor activating agents. J Clin Oncol. 2005;23:9394–407.

    Article  CAS  Google Scholar 

  22. Schulze-Bergkamen H, Krammer PH. Apoptosis in cancer-implications for therapy. Semin Oncol. 2004;31:90–119.

    Article  CAS  Google Scholar 

  23. Sun SY, Hail N Jr, Lotan R. Apoptosis as a novel target for cancer chemoprevention. J Natl Cancer Inst. 2004;96:662–72.

    Article  CAS  Google Scholar 

  24. Zhang L, Lu Z, Zhao X. Targeting Bcl-2 for cancer therapy. Biochim Biophys Acta Rev Cancer. 2021;1876:188569.

    Article  CAS  Google Scholar 

  25. Shi P, Oh YT, Zhang G, Yao W, Yue P, Li Y, et al. Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment. Cancer Lett. 2016;380:494–504.

    Article  CAS  Google Scholar 

  26. Sun SY, Yue P, Dawson MI, Shroot B, Michel S, Lamph WW, et al. Differential effects of synthetic nuclear retinoid receptor-selective retinoids on the growth of human non-small cell lung carcinoma cells. Cancer Res. 1997;57:4931–9.

    CAS  PubMed  Google Scholar 

  27. Zong D, Gu J, Cavalcante GC, Yao W, Zhang G, Wang S, et al. BRD4 levels determine the response of human lung cancer cells to BET degraders that potently induce apoptosis through suppression of Mcl-1. Cancer Res. 2020;80:2380–93.

    Article  CAS  Google Scholar 

  28. Hasenjager A, Gillissen B, Muller A, Normand G, Hemmati PG, Schuler M, et al. Smac induces cytochrome c release and apoptosis independently from Bax/Bcl-x(L) in a strictly caspase-3-dependent manner in human carcinoma cells. Oncogene. 2004;23:4523–35.

    Article  Google Scholar 

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Acknowledgements

We thank Dr. A. Hammond in our department for editing the manuscript. This work was supported by Emory University Winship Cancer Institute lung cancer pilot fund (to SYS), NIH/NCI SPORE P50 CA217691 (to XD) and a research fund from Ascentage Pharma (to SYS). TKO, SSR and SYS are Georgia Research Alliance Distinguished Cancer Scientists.

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Authors and Affiliations

  1. Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Guangzhi Ma

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

    Guangzhi Ma, Yunfu Deng, Luxi Qian, Karin A. Vallega, Guojing Zhang, Suresh S. Ramalingam & Shi-Yong Sun

  3. Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Yunfu Deng

  4. Department of Radiation Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

    Luxi Qian

  5. Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA

    Xingming Deng

  6. Department of Medicine, University of Pittsburgh and Hillman Cancer Center, Pittsburgh, PA, USA

    Taofeek K. Owonikoko

  7. Ascentage Pharma (Suzhou) Co., Ltd, Suzhou, Jiangsu, China

    Douglas D. Fang & Yifan Zhai

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Contributions

Conceptualization: GM, XD, TKO, SSR, DDF, YZ, and S-YS. Investigation: GM, YD, LQ, KAV, and GZ. Methodology: GM, YD, LQ, KAV, GZ and S-YS. Writing/Original Draft: GM, and S-YS. Review/Editing: YD, LQ, KAV, GZ, XD, TKO, SSR, DDF, and YZ. Funding Acquisition: SSR, XD, DDF, YZ and S-YS. Supervision: XD, YZ, and S-YS.

Corresponding author

Correspondence to Shi-Yong Sun.

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Competing interests

TKO is on consulting/advisory board for Novartis, Celgene, Lilly, Sandoz, Abbvie, Eisai, Takeda, Bristol-Myers Squibb, MedImmune, Amgen, AstraZeneca and Boehringer Ingelheim. SSR is on consulting/advisory board for AstraZeneca, BMS, Merck, Roche, Tesaro and Amgen. YZ and DDF are full-time employees and equity shareholders of Ascentage Pharma. SYS received a research fund from Ascentage Pharma. Other authors disclose that they have no potential conflicts of interest.

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Ma, G., Deng, Y., Qian, L. et al. Overcoming acquired resistance to third-generation EGFR inhibitors by targeting activation of intrinsic apoptotic pathway through Mcl-1 inhibition, Bax activation, or both. Oncogene 41, 1691–1700 (2022). https://doi.org/10.1038/s41388-022-02200-5

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