Targeting the differential addiction to anti-apoptotic BCL-2 family for cancer therapy

Akane Inoue-Yamauchi, Paul S. Jeng, Kwanghee Kim, Hui-Chen Chen, Song Han, Yogesh Tengarai Ganesan, Kota Ishizawa, Sylvia Jebiwott, Yiyu Dong, Maria C. Pietanza, Matthew D. Hellmann, Mark G. Kris, James J. Hsieh and Emily H. Cheng ()
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Akane Inoue-Yamauchi: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Paul S. Jeng: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Kwanghee Kim: Memorial Sloan Kettering Cancer Center
Hui-Chen Chen: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Song Han: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Yogesh Tengarai Ganesan: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Kota Ishizawa: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Sylvia Jebiwott: Memorial Sloan Kettering Cancer Center
Yiyu Dong: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Maria C. Pietanza: Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center
Matthew D. Hellmann: Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center
Mark G. Kris: Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center
James J. Hsieh: Molecular Oncology, Siteman Cancer Center, Washington University
Emily H. Cheng: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract BCL-2 family proteins are central regulators of mitochondrial apoptosis and validated anti-cancer targets. Using small cell lung cancer (SCLC) as a model, we demonstrated the presence of differential addiction of cancer cells to anti-apoptotic BCL-2, BCL-XL or MCL-1, which correlated with the respective protein expression ratio. ABT-263 (navitoclax), a BCL-2/BCL-XL inhibitor, prevented BCL-XL from sequestering activator BH3-only molecules (BH3s) and BAX but not BAK. Consequently, ABT-263 failed to kill BCL-XL-addicted cells with low activator BH3s and BCL-XL overabundance conferred resistance to ABT-263. High-throughput screening identified anthracyclines including doxorubicin and CDK9 inhibitors including dinaciclib that synergized with ABT-263 through downregulation of MCL-1. As doxorubicin and dinaciclib also reduced BCL-XL, the combinations of BCL-2 inhibitor ABT-199 (venetoclax) with doxorubicin or dinaciclib provided effective therapeutic strategies for SCLC. Altogether, our study highlights the need for mechanism-guided targeting of anti-apoptotic BCL-2 proteins to effectively activate the mitochondrial cell death programme to kill cancer cells.

Date: 2017
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DOI: 10.1038/ncomms16078

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