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

<b>Purpose:</b> 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.<b>Experimental Design:</b> 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.<b>Results:</b> 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 <i>in vitro</i> and blocked tumor growth and induced tumor regressions in mice bearing high BCL-2-expressing SCLC tumors <i>in vivo</i> 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.<b>Conclusions:</b> Altogether, our findings identify venetoclax as a promising new therapy for high BCL-2-expressing SCLCs. <i>Clin Cancer Res; 24(2); 360-9. ©2017 AACR</i>.