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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.

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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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  1. Guangzhi Ma
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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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