Abstract
Abstract High-grade serous ovarian carcinoma (HGS-OvCa) is the most common and deadly form of ovarian cancer, and currently lacks effective targeted therapies. Recently, proteins involved in chromatin remodeling such as the BET bromodomain protein BRD4 have emerged as an exciting new class of targets for the treatment of cancer. Targeted BRD4 inhibition has been shown to cause tumor regression and apoptosis in a number of cancers, including HGS-OvCa. Consequently, small molecule BET bromodomain inhibitors (BETi) are actively being pursued in clinical trials. In our preliminary studies, we discovered that the BET inhibitor JQ1 dramatically reduced MYC protein levels resulting in inhibited cell growth and survival in a panel of HGS-OvCa cell lines. Importantly, although JQ1 initially caused significant growth arrest and apoptosis, the majority of HGS-OvCa cell lines acquired drug resistance. Detailed molecular characterization of JQ1- resistant HGS-OvCa cells showed the return of MYC protein levels accompanied by elevated PI3K-AKT activity, suggesting the acquired resistance stems from activated kinase signaling. Our laboratory has designed a novel mass spectrometry approach that globally measures kinase activity to identify the kinase networks responsible for drug resistance. Using this technology, we analyzed global kinase activity in JQ1-resistant cells and observed the activation of several receptor-tyrosine kinases (RTKs), including EGFR, FGFRs and IGF1R known to strongly drive PI3K-AKT pro-survival signaling pathways. These findings suggest that BETi therapies may have limited success as single agent therapies due to “adaptive kinome reprogramming” and will likely require combination strategies involving inhibitors targeting protein kinases and BET bromodomain proteins. Citation Format: Alison M. Kurimchak, Claude Shelton, Kelly E. Duncan, Katherine J. Johnson, Jennifer Brown, Shane O'Brien, Rashid Gabbasov, Lauren S. Fink, Yuesheng Li, Nicole Lounsbury, Magid Abou-Gharbia, Wayne E. Childers, Denise C. Connolly, Jonathan Chernoff, Jeffrey R. Peterson, James S. Duncan. DYNAMIC REPROGRAMMING OF THE KINOME OVERCOMES BET PROTEIN INHIBITION IN OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-087.
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