Format

Send to

Choose Destination
Nat Commun. 2017 Jul 17;8:16078. doi: 10.1038/ncomms16078.

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

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
2
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
3
Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
4
Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
5
Molecular Oncology, Department of Medicine, Siteman Cancer Center, Washington University, St Louis, Missouri 63110, USA.
6
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
7
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, New York 10065, USA.

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center