Abstract 4709: Broad activity for the combination of BET and MEK inhibitors across solid and hematologic cancers

Abstract

BET (bromodomain and extra-terminal) family proteins are epigenetic readers that modulate expression 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 chromatin and inhibit transcription of BET target genes. We and others have previously demonstrated single agent activity for BET inhibitors in a number of pre-clinical solid and hematologic tumor models. Transcriptomics and mechanistic studies from several of these tumor types indicate that BET inhibitors influence numerous signaling pathways at the transcriptional level, including RAS/RAF/MEK signaling. Here we describe the synergistic effects of combining BET and MEK inhibitors in various solid and hematologic cancer models. We observe synergistic growth inhibition and apoptosis in a subset of cell lines representing multiple tumor types, as well as patient-derived xenograft models treated with the combination ex vivo. Additionally, combination of BET and MEK inhibitors results in improved tumor growth inhibition in cell line xenograft models compared to either single agent therapy. Further exploration of the combination in sensitive tumor types highlights multiple mechanisms potentially driving synergy, and suggests possible markers associated with sensitivity to the combination. Taken together, our data highlight the potential of BET/MEK inhibitor combinations to improve upon the efficacy observed for these agents as monotherapies in a wide variety of preclinical cancer models. 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. Human biological samples were sourced ethically and their research use was in accord with the terms of the informed consents. Citation Format: Anastasia Wyce, Daniel J. Felitsky, Xi-Ping Zhang, Jeanne J. Matteo, Susan Korenchuk, Lijoy K. Mathew, Melissa Musso, Sakina Khaku, Victoria Ortiz, Kathryn Keenan, Melissa Stern, Yan Degenhardt, Ramona Plant, Charles F. McHugh, Peter J. Tummino, Christopher Carpenter, Olena Barbash. Broad activity for the combination of BET and MEK inhibitors across solid and hematologic cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4709.