@article{c4bbee179b8f4be0aa29a10f29f59dba,
title = "Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer",
abstract = "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.",
author = "Shaokun Shu and Lin, {Charles Y.} and He, {Housheng Hansen} and Witwicki, {Robert M.} and Tabassum, {Doris P.} and Roberts, {Justin M.} and Michalina Janiszewska and Huh, {Sung Jin} and Yi Liang and Jeremy Ryan and Ernest Doherty and Hisham Mohammed and Hao Guo and Stover, {Daniel G.} and Ekram, {Muhammad B.} and Guillermo Peluffo and Jonathan Brown and Clive D'Santos and Krop, {Ian E.} and Deborah Dillon and Michael McKeown and Christopher Ott and Jun Qi and Min Ni and Rao, {Prakash K.} and Melissa Duarte and Wu, {Shwu Yuan} and Chiang, {Cheng Ming} and Lars Anders and Young, {Richard A.} and Winer, {Eric P.} and Antony Letai and Barry, {William T.} and Carroll, {Jason S.} and Long, {Henry W.} and Myles Brown and Liu, {X. Shirley} and Meyer, {Clifford A.} and Bradner, {James E.} and Kornelia Polyak",
note = "Funding Information: Acknowledgements We thank D. Silver and members of the Polyak and Bradner laboratories for their critical reading of this manuscript and useful discussions. We thank G. Brown for help with creating the word cloud figures. This work was supported by the NIH DF/HCC SPORE in Breast Cancer CA168504 (K.P., E.P.W., I.E.K., D.D., W.T.B., and J.E.B.), CA080111 (K.P. and M.B.), and CA103867 (C.M.C.), Susan G. Komen Foundation (S.S.), CPRIT RP110471 and RP140367 (C.M.C), Welch Foundation (C.M.C.), US Department of Defense CDMRP BC122003 (S.X.L.) and CA120184 (C.Y.L.), Princess Margaret Cancer Foundation (H.H.H.), Canada Foundation for Innovation and Ontario Research Fund CFI32372 (H.H.H.), NSERC discovery grant RGPIN-2015-04658 (H.H.H.), and the Harvard Ludwig Center for Cancer Research (J.E.B., M.B. and K.P.). Publisher Copyright: {\textcopyright} 2016 Macmillan Publishers Limited. All rights reserved.",
year = "2016",
month = jan,
day = "21",
doi = "10.1038/nature16508",
language = "English (US)",
volume = "529",
pages = "413--417",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7586",
}