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Venetoclax Is Effective in Small-Cell Lung Cancers with High BCL-2 Expression
Timothy L Lochmann1, Konstantinos V Floros1, Mitra Naseri1
1VCU Philips Institute, School of Dentistry and Massey Cancer Center; Richmond, Virginia.
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.
Insights
Venetoclax, a BCL-2 inhibitor, shows promise for treating small-cell lung cancer (SCLC). This drug effectively targets SCLC cells with high BCL-2 expression, inducing apoptosis and inhibiting tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Small-cell lung cancer (SCLC) is an aggressive neuroendocrine cancer with poor prognosis.
- Limited therapeutic options exist for SCLC due to a lack of druggable targets.
- Advances in SCLC genomics have yet to translate into effective new treatments.
Purpose of the Study:
- To identify a venetoclax-sensitive subpopulation within SCLC.
- To investigate the efficacy of venetoclax as a potential SCLC therapy.
- To explore biomarkers predicting venetoclax sensitivity in SCLC.
Main Methods:
- High-throughput drug screening of SCLC cell lines with venetoclax.
- Validation using patient-derived xenografts (PDX) of SCLC.
- Assessment of BCL-2 expression as a predictive biomarker.
- Investigation of gene methylation's role in SCLC classification.
Main Results:
- Venetoclax demonstrated activity in a significant fraction of SCLC cell lines.
- Venetoclax induced BIM-dependent apoptosis in vitro and inhibited tumor growth in vivo.
- High BCL-2 expression served as a predictive biomarker for venetoclax sensitivity.
- Gene methylation patterns were identified that distinguish high BCL-2-expressing SCLCs.
Conclusions:
- Venetoclax is a promising therapeutic agent for SCLC patients with high BCL-2 expression.
- Targeting BCL-2 offers a potential new strategy for treating SCLC.
- Further research into venetoclax and BCL-2 pathways in SCLC is warranted.
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