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

Clinical Cancer Research - Tập 24 Số 2 - Trang 360-369 - 2018
Timothy L. Lochmann1, Konstantinos V. Floros1, Mitra Naseri1, Krista M. Powell1, Wade Cook1, Ryan J. March2, Giovanna T. Stein2, Patricia Greninger2, Yuki Kato Maves3, Laura R. Saunders4, Scott J. Dylla4, Carlotta Costa2, Sosipatros A. Boikos5, Joel D. Leverson6, Andrew J. Souers6, Geoffrey W. Krystal7, Hisashi Harada1, Cyril H. Benes2, Anthony C. Faber1
11VCU Philips Institute, School of Dentistry and Massey Cancer Center; Richmond, Virginia.
22Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
33Crown Bioscience Inc, San Diego, California.
44AbbVie Stemcentrx LLC, South San Francisco, California.
55Division of Hematology, Oncology, & Palliative Care, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
66AbbVie, North Chicago, Illinois.
77Department of Internal Medicine, Virginia Commonwealth University, McGuire Veterans Affairs Medical Center, Richmond, Virginia.

Tóm tắt

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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Clinical Cancer Research

Tập 24 Số 2

360-369

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