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Transient targeting of BIM-dependent adaptive MCL1 preservation enhances tumor response to molecular therapeutics in non-small cell lung cancer

Cell Death & Differentiation volume 30, pages 195–207 (2023)Cite this article

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Abstract

Despite remarkable efficacy, targeted treatments often yield a subpopulation of residual tumor cells in part due to non-genetic adaptions. Previous mechanistic understanding on the emergence of these drug-tolerant persisters (DTPs) has been limited to epigenetic and transcriptional reprogramming. Here, by comprehensively interrogating therapy-induced early dynamic protein changes in diverse oncogene-addicted non-small cell lung cancer models, we identified adaptive MCL1 increase as a new and universal mechanism to confer apoptotic evasion and DTP formation. In detail, acute MAPK signaling disruption in the presence of genotype-based tyrosine kinase inhibitors (TKIs) prompted mitochondrial accumulation of pro-apoptotic BH3-only protein BIM, which sequestered MCL1 away from MULE-mediated degradation. A small-molecule combination screen uncovered that PI3K-mTOR pathway blockade prohibited MCL1 upregulation. Biochemical and immunocytochemical evidence indicated that mTOR complex 2 (mTORC2) bound and phosphorylated MCL1, facilitating its interaction with BIM. As a result, short-term polytherapy combining antineoplastic TKIs with PI3K, mTOR or MCL1 inhibitors sufficed to prevent DTP development and promote cancer eradication. Collectively, these findings support that upfront and transient targeting of BIM-dependent, mTORC2-regulated adaptive MCL1 preservation holds enormous promise to improve the therapeutic index of molecular targeted agents.

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Fig. 1: Adaptive MCL1 upregulation in response to molecular targeted therapies.
Fig. 2: Genetic or pharmacological MCL1 inhibition enhances tumor response to molecular therapeutics.
Fig. 3: Molecular targeted therapies induce BIM-dependent MCL1 preservation.
Fig. 4: BIM-associated adaptive MCL1 preservation is tuned by mTORC2-mediated MCL1 phosphorylation.
Fig. 5: Transient targeting of adaptive MCL1 preservation provokes tumor cell death.
Fig. 6: Transient targeting of adaptive MCL1 preservation may be exploited to augment therapeutic efficacy in vivo.

Data availability

All original data are available upon request from the authors.

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Acknowledgements

We acknowledge all lab members for technical support and helpful discussions. This work was supported by the National Natural Science Foundation of China (81922047 and 82172596 to GZ; 82072560 to XZ), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20161313 to GZ), Shanghai Collaborative Innovation Center for Translational Medicine (TM202005 to GZ), and innovative research team of high-level local universities in Shanghai (SHSMU-ZLCX20210200 to GZ).

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Author notes

  1. These authors contributed equally: Kaixuan Shi, Haijiao Lu, Zhenfeng Zhang, Yujie Fu, Jie Wu.

Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Kaixuan Shi, Zhenfeng Zhang, Shichao Zhou, Kaiyan Ye, Shengzhe Zhang, Mei-Chun Cai & Guanglei Zhuang

  2. Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China

    Haijiao Lu

  3. Department of Thoracic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Yujie Fu, Pengfei Ma, Xiaojing Zhao & Jian Tang

  4. Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China

    Jie Wu, Hailei Shi & Weiping Shi

  5. Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China

    Zhuang Yu

  6. Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Guanglei Zhuang

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Contributions

GZ, JT, ZY, and XZ conceptualized the study. KS, HL, ZZ, YF, JW, SZ, PM, KY, SZ, HS and WS conducted the experiments and analyzed the data. KS and M-CC performed the bioinformatics analyses. GZ and KS wrote the manuscript. All the authors read and approved the manuscript.

Corresponding authors

Correspondence to Xiaojing Zhao, Zhuang Yu, Jian Tang or Guanglei Zhuang.

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The institutional animal care and use committee of Ren Ji Hospital approved animal protocols. The study using human tissues was approved by the Ethics Committee of Ren Ji Hospital and all patients signed informed consent.

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Shi, K., Lu, H., Zhang, Z. et al. Transient targeting of BIM-dependent adaptive MCL1 preservation enhances tumor response to molecular therapeutics in non-small cell lung cancer. Cell Death Differ 30, 195–207 (2023). https://doi.org/10.1038/s41418-022-01064-2

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