Venetoclax Is Effective in Small-Cell Lung Cancers with High BCL-2 Expression.

Clin Cancer Res 2018 01 8;24(2):360-369. Epub 2017 Nov 8.

VCU Philips Institute, School of Dentistry and Massey Cancer Center; Richmond, Virginia.

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. 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. 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 and blocked tumor growth and induced tumor regressions in mice bearing high BCL-2-expressing SCLC tumors 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. Altogether, our findings identify venetoclax as a promising new therapy for high BCL-2-expressing SCLCs. .

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Source
http://dx.doi.org/10.1158/1078-0432.CCR-17-1606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771805PMC
January 2018
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