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

Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy(1-3). BET bromodomain inhibitors, which have shown efficacy in several models of cancer(4-6), have not been evaluated in TNBC. These inhibitors displace BET bromodomain pr...

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Autores principales: Shu, Shaokun, Lin, Charles Y., He, Housheng Hansen, Witwicki, Robert M., Tabassum, Doris P., Roberts, Justin M., Janiszewska, Michalina, Huh, Sung Jin, Liang, Yi, Ryan, Jeremy, Doherty, Ernest, Mohammed, Hisham, Guo, Hao, Stover, Daniel G., Ekram, Muhammad B., Brown, Jonathan, D'Santos, Clive, Krop, Ian E., Dillon, Deborah, McKeown, Michael, Ott, Christopher, Qi, Jun, Ni, Min, Rao, Prakash K., Duarte, Melissa, Wu, Shwu-Yuan, Chiang, Cheng-Ming, Anders, Lars, Young, Richard A., Winer, Eric, Letai, Antony, Barry, William T., Carroll, Jason S., Long, Henry, Brown, Myles, Liu, X. Shirley, Meyer, Clifford A., Bradner, James E., Polyak, Kornelia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854653/
https://www.ncbi.nlm.nih.gov/pubmed/26735014
http://dx.doi.org/10.1038/nature16508
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author Shu, Shaokun
Lin, Charles Y.
He, Housheng Hansen
Witwicki, Robert M.
Tabassum, Doris P.
Roberts, Justin M.
Janiszewska, Michalina
Huh, Sung Jin
Liang, Yi
Ryan, Jeremy
Doherty, Ernest
Mohammed, Hisham
Guo, Hao
Stover, Daniel G.
Ekram, Muhammad B.
Brown, Jonathan
D'Santos, Clive
Krop, Ian E.
Dillon, Deborah
McKeown, Michael
Ott, Christopher
Qi, Jun
Ni, Min
Rao, Prakash K.
Duarte, Melissa
Wu, Shwu-Yuan
Chiang, Cheng-Ming
Anders, Lars
Young, Richard A.
Winer, Eric
Letai, Antony
Barry, William T.
Carroll, Jason S.
Long, Henry
Brown, Myles
Liu, X. Shirley
Meyer, Clifford A.
Bradner, James E.
Polyak, Kornelia
author_facet Shu, Shaokun
Lin, Charles Y.
He, Housheng Hansen
Witwicki, Robert M.
Tabassum, Doris P.
Roberts, Justin M.
Janiszewska, Michalina
Huh, Sung Jin
Liang, Yi
Ryan, Jeremy
Doherty, Ernest
Mohammed, Hisham
Guo, Hao
Stover, Daniel G.
Ekram, Muhammad B.
Brown, Jonathan
D'Santos, Clive
Krop, Ian E.
Dillon, Deborah
McKeown, Michael
Ott, Christopher
Qi, Jun
Ni, Min
Rao, Prakash K.
Duarte, Melissa
Wu, Shwu-Yuan
Chiang, Cheng-Ming
Anders, Lars
Young, Richard A.
Winer, Eric
Letai, Antony
Barry, William T.
Carroll, Jason S.
Long, Henry
Brown, Myles
Liu, X. Shirley
Meyer, Clifford A.
Bradner, James E.
Polyak, Kornelia
author_sort Shu, Shaokun
collection PubMed
description Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy(1-3). BET bromodomain inhibitors, which have shown efficacy in several models of cancer(4-6), have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyllysine recognition modules, leading to inhibition of oncogenic transcriptional programs(7-9). 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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spelling pubmed-48546532016-07-06 Response and resistance to BET bromodomain inhibitors in triple negative breast cancer Shu, Shaokun Lin, Charles Y. He, Housheng Hansen Witwicki, Robert M. Tabassum, Doris P. Roberts, Justin M. Janiszewska, Michalina Huh, Sung Jin Liang, Yi Ryan, Jeremy Doherty, Ernest Mohammed, Hisham Guo, Hao Stover, Daniel G. Ekram, Muhammad B. Brown, Jonathan D'Santos, Clive Krop, Ian E. Dillon, Deborah McKeown, Michael Ott, Christopher Qi, Jun Ni, Min Rao, Prakash K. Duarte, Melissa Wu, Shwu-Yuan Chiang, Cheng-Ming Anders, Lars Young, Richard A. Winer, Eric Letai, Antony Barry, William T. Carroll, Jason S. Long, Henry Brown, Myles Liu, X. Shirley Meyer, Clifford A. Bradner, James E. Polyak, Kornelia Nature Article Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy(1-3). BET bromodomain inhibitors, which have shown efficacy in several models of cancer(4-6), have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyllysine recognition modules, leading to inhibition of oncogenic transcriptional programs(7-9). 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. 2016-01-06 2016-01-21 /pmc/articles/PMC4854653/ /pubmed/26735014 http://dx.doi.org/10.1038/nature16508 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Shu, Shaokun
Lin, Charles Y.
He, Housheng Hansen
Witwicki, Robert M.
Tabassum, Doris P.
Roberts, Justin M.
Janiszewska, Michalina
Huh, Sung Jin
Liang, Yi
Ryan, Jeremy
Doherty, Ernest
Mohammed, Hisham
Guo, Hao
Stover, Daniel G.
Ekram, Muhammad B.
Brown, Jonathan
D'Santos, Clive
Krop, Ian E.
Dillon, Deborah
McKeown, Michael
Ott, Christopher
Qi, Jun
Ni, Min
Rao, Prakash K.
Duarte, Melissa
Wu, Shwu-Yuan
Chiang, Cheng-Ming
Anders, Lars
Young, Richard A.
Winer, Eric
Letai, Antony
Barry, William T.
Carroll, Jason S.
Long, Henry
Brown, Myles
Liu, X. Shirley
Meyer, Clifford A.
Bradner, James E.
Polyak, Kornelia
Response and resistance to BET bromodomain inhibitors in triple negative breast cancer
title Response and resistance to BET bromodomain inhibitors in triple negative breast cancer
title_full Response and resistance to BET bromodomain inhibitors in triple negative breast cancer
title_fullStr Response and resistance to BET bromodomain inhibitors in triple negative breast cancer
title_full_unstemmed Response and resistance to BET bromodomain inhibitors in triple negative breast cancer
title_short Response and resistance to BET bromodomain inhibitors in triple negative breast cancer
title_sort response and resistance to bet bromodomain inhibitors in triple negative breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854653/
https://www.ncbi.nlm.nih.gov/pubmed/26735014
http://dx.doi.org/10.1038/nature16508
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