Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer

Shaokun Shu, Charles Y Lin, Housheng Hansen He, Robert M Witwicki, Doris P Tabassum, Justin M Roberts, Michalina Janiszewska, Sung Jin Huh, Yi Liang, Jeremy Ryan, Ernest Doherty, Hisham Mohammed, Hao Guo, Daniel G Stover, Muhammad B Ekram, Jonathan Brown, Clive D'Santos, Ian E Krop, Deborah Dillon, Michael McKeown, Christopher Ott, Jun Qi, Min Ni, Prakash K Rao, Melissa Duarte, Shwu-Yuan Wu, Cheng-Ming Chiang, Lars Anders, Richard A Young, Eric Winer, Antony Letai, William T Barry, Jason S Carroll, Henry Long, Myles Brown, X Shirley Liu, Clifford A Meyer, James E Bradner, Kornelia Polyak
Nature 2016 January 21, 529 (7586): 413-417
Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance.

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