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Clin Cancer Res. 2018 Jan 15;24(2):360-369. doi: 10.1158/1078-0432.CCR-17-1606. Epub 2017 Nov 8.

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

Author information

1
VCU Philips Institute, School of Dentistry and Massey Cancer Center; Richmond, Virginia.
2
Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
3
Crown Bioscience Inc, San Diego, California.
4
AbbVie Stemcentrx LLC, South San Francisco, California.
5
Division of Hematology, Oncology, & Palliative Care, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
6
AbbVie, North Chicago, Illinois.
7
Department of Internal Medicine, Virginia Commonwealth University, McGuire Veterans Affairs Medical Center, Richmond, Virginia.
8
VCU Philips Institute, School of Dentistry and Massey Cancer Center; Richmond, Virginia. acfaber@vcu.edu cbenes@mgh.harvard.edu hharada@vcu.edu.
9
Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts. acfaber@vcu.edu cbenes@mgh.harvard.edu hharada@vcu.edu.

Abstract

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. Clin Cancer Res; 24(2); 360-9. ©2017 AACR.

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