Abstract B34: Novel synergistic combination therapies with BET bromodomain inhibitors in triple-negative breast cancer

Adaptive resistance to targeted cancer therapies is a universal problem in cancer treatment where tumor cells circumvent targeted pathway inhibition to reactivate growth signaling. In our previous work, we observed genome-wide enhancer remodeling following MEK inhibition (MEKi) capable of driving adaptive gene transcription in triple-negative breast cancer (TNBC). Adaptive enhancers were enriched for the BET bromodomain protein BRD4 and cotreatment with MEKi and BET inhibitor (JQ1) could durably suppress TNBC growth in multiple cell lines and preclinical mouse models. There are currently 10 BET inhibitors in clinical trials being tested as single agents across multiple tumor types including TNBC. There is also a growing body of preclinical literature using epigenetic inhibitors to block the adaptive ability of tumor cells in combination with multiple targeted therapies. This led us to screen for inhibitors that synergize with JQ1 to suppress growth of TNBC using a 176-compound library enriched for epigenetic and kinase inhibitors. We performed synergy screens in 6 TNBC cell lines across 6 doses of JQ1 and each library compound. Using the Bliss Independence model to assess synergy, we found that inhibition of MEK, CDK9, Aurora Kinase, CREBBP/P300, and BAZ2A/B was strongly synergistic with JQ1. BRD4, CDK9, and the acetyltransferase CREBBP/P300 are all members of the P-TEFb transcriptional elongation complex. When we performed additional synergy screens against the P300 bromodomain inhibitor CPI-637, we found a significant overlap in synergistic targets with the JQ1 screen including MEK, BET bromodomain proteins, ERK, Aurora Kinase, and CDK9. BAZ2A/B inhibition using the small-molecule inhibitor GSK2801, which targets the bromodomain of BAZ2A/B, synergized significantly stronger with JQ1 across all cell lines compared to CPI637. BAZ2A/B proteins are members of nucleosome remodeling complexes that mediate DNA silencing by aiding in recruitment of histone modifying enzymes. Ongoing studies seek to understand the role of BAZ2A/B and the mechanism of GSK2801 synergy with BET bromodomain inhibition using RNA sequencing and ChIP sequencing experiments. These results define novel targets that synergize with JQ1 to suppress tumor cell growth and illuminate additional mechanisms of transcriptional regulation driven by BET bromodomain proteins in TNBC. Citation Format: Samantha M. Bevill, Noah Sciaky, Brian T. Golitz, Naim U. Rashid, Jon S. Zawistowski, Gary L. Johnson. Novel synergistic combination therapies with BET bromodomain inhibitors in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B34.