Abstract 2867: Inhibition of BET bromodomain proteins as a therapeutic approach in small cell lung cancer

Abstract

Abstract BET (bromodomain and extra-terminal) family proteins are epigenetic readers that regulate expression of genes involved in cell growth and oncogenesis. Selective small molecule BET inhibitors, such as the GSK I-BETs (I-BET762, I-BET151), abrogate binding of BET proteins to acetylated histones and inhibit transcriptional activation of BET target genes. BET inhibitors attenuate proliferation and survival in a number of hematologic cancer models, partially through down-regulation of the critical oncogene, MYC. We and others have previously shown activity for BET inhibitors in solid tumor models such as neuroblastoma and prostate cancer, with concomitant down-regulation of MYC family gene expression. However, MYC or MYCN silencing only partially accounts for the activity of BET inhibitors in these models, suggesting that transcriptional regulation of multiple pathways promotes I-BET induced phenotypes. Here we describe the activity of the selective BET inhibitor, I-BET762, in small cell lung cancer (SCLC), a highly aggressive malignancy with few treatment options. We observe potent growth inhibition and apoptosis in a subset of cell lines and patient-derived SCLC models in vitro, as well as significant tumor growth inhibition in cell line and primary mouse xenografts. These anti-proliferative effects are likely mediated by inhibition of BRD2, BRD3, and BRD4, as siRNAs individually targeting all three proteins result in partial inhibition of SCLC cell line growth. Similar to our observations in neuroblastoma and prostate cancer, I-BET762 treatment in SCLC cell lines results in transcriptional changes affecting MYC and other pathways. We explore the contribution of these changes to the anti-proliferative effects observed in SCLC models, and identify potential combination strategies to enhance the activity of I-BET762. Taken together, our data highlight the potential of BET inhibitors as novel therapeutic agents to treat small cell lung cancer driven by various oncogenic pathways. All studies were conducted in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals and were reviewed by the Institutional Animal Care and Use Committee either at GSK or by the ethical review process at the institution where the work was performed. Citation Format: Anastasia Wyce, BaoChau Le, Yuchen Bai, David Soong, Xi-Ping Zhang, Jeanne J. Matteo, Susan Korenchuk, Michael F. Butticello, Ramona Plant, Maureen R. Bleam, Yan Degenhardt, Charles F. McHugh, Christopher Carpenter, Peter J. Tummino, Olena Barbash. Inhibition of BET bromodomain proteins as a therapeutic approach in small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2867. doi:10.1158/1538-7445.AM2015-2867