Abstract LB-40: Induciblein vivosilencing of Brd4 identifies potential toxicities of sustained BET protein inhibition

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA BET family proteins are novel therapeutic targets for cancer and inflammation and represent the first epigenetic readers against which small-molecule inhibitors have been developed. First generation BET inhibitors have shown some therapeutic efficacy in pre-clinical models, however the consequences of disrupting BET protein function in normal tissues are largely unknown. Using an inducible and reversible transgenic RNAi mouse model targeting the BET family protein Brd4, we show that acute suppression of Brd4 in adult animals has immediate and dramatic effects in multiple tissues. Brd4-depleted mice displayed epidermal hyperplasia, alopecia, and decreased cellular diversity and stem cell depletion in the small intestine. To test whether the loss of intestinal stem cells induced by Brd4 suppression would have consequences in combination with agents that induce acute gut toxicity, we subjected mice to a sub-lethal irradiation. Whereas control mice showed intestinal recovery 4-5 days following irradiation, Brd4-depleted mice showed dramatic and continued crypt-villus atrophy, implying that potent BET protein inhibition in combination with cytotoxic chemotherapy may show significantly enhanced toxicity in the clinic. These findings provide important insight into Brd4 function in normal tissues and importantly, predict several potential outcomes associated with potent and sustained inhibition of BET protein function. Citation Format: Jessica Bolden, Nilgun Tasdemir, Lukas Dow, Johan H. van Es, John E. Wilkinson, Zhen Zhao, Hans Clevers, Scott W. Lowe. Inducible in vivo silencing of Brd4 identifies potential toxicities of sustained BET protein inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-40. doi:10.1158/1538-7445.AM2014-LB-40