Abstract 406: Enhancer templated RNAs as predictors of therapeutic response to epigenetic therapy

Abstract

Abstract Colon tumors arise in a stepwise fashion from either discrete genetic perturbations or epigenetic dysregulation. To uncover the key epigenetic regulators that drive colon cancer growth, we utilized a CRISPR loss of function screen and identified a number of essential genes, including the Bromodomain and Extraterminal (BET) protein, BRD4. We find BRD4 is critical for colon cancer proliferation and its loss leads to differentiation effects in vivo. JQ1, a BET inhibitor, preferentially reduced growth in a subset of epigenetically dysregulated colon cancers, characterized by the CpG island methylator phenotype (CIMP). Integrated transcriptomic and genomic analyses defined a distinct super-enhancer in CIMP(+) colon cancers that regulates cMYC transcription. We find that the CCAT1 long non-coding RNA (lncRNA) is transcribed from this super-enhancer and is exquisitely sensitive to BET inhibition. Concordantly, cMYC transcription and cell growth were tightly correlated with the presence of CCAT1 RNA in a variety of tumor types. Taken together, we propose CCAT1 as a clinically tractable biomarker for identifying patients likely to benefit from BET inhibitors. Citation Format: Ron Firestein, Mark McCleland, Kathryn Mesh, Florian Gnad. Enhancer templated RNAs as predictors of therapeutic response to epigenetic therapy. [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 406.