Journal
CLINICAL CANCER RESEARCH
Volume 24, Issue 2, Pages 360-369Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-17-1606
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Funding
- NIH-NCI Cancer Center Support Grant [P30-CA016059, 5P30CA016059-35]
- National Cancer Institute [K22-CA175276]
- Wellcome Trust [102696]
- George and Lavinia Blick Research Fund
- Harrison Endowed Scholar in Cancer Research
- NIH-NCI Cancer Center Support [P30-CA016059]
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Purpose: Small-cell lung cancer (SCLC) is an often-fatal neuroendocrine carcinoma usually presenting as extensive disease, carrying a 3% 5-year survival. Despite notable advances in SCLC genomics, new therapies remain elusive, largely due to a lack of druggable targets. Experimental Design: We used a high-throughput drug screen to identify a venetoclax-sensitive SCLC subpopulation and validated the findings with multiple patient-derived xenografts of SCLC. Results: Our drug screen consisting of a very large collection of cell lines demonstrated that venetoclax, an FDA-approved BCL-2 inhibitor, was found to be active in a substantial fraction of SCLC cell lines. Venetoclax induced BIM-dependent apoptosis in vitro and blocked tumor growth and induced tumor regressions in mice bearing high BCL-2-expressing SCLC tumors in vivo. BCL-2 expression was a predictive biomarker for sensitivity in SCLC cell lines and was highly expressed in a subset of SCLC cell lines and tumors, suggesting that a substantial fraction of patients with SCLC could benefit from venetoclax. Mechanistically, we uncover a novel role for gene methylation that helped discriminate high BCL-2-expressing SCLCs. Conclusions: Altogether, our findings identify venetoclax as a promising new therapy for high BCL-2-expressing SCLCs. (C) 2017 AACR.
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