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. 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...
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2017
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| Online Access: | http://hdl.handle.net/1721.1/109131 |
| _version_ | 1826206947545710592 |
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| author | Shu, Shaokun Lin, Charles Y. He, Housheng Hansen Witwicki, Robert M. Tabassum, Doris P. Roberts, Justin M. Janiszewska, Michalina Jin Huh, Sung Liang, Yi Ryan, Jeremy Doherty, Ernest Mohammed, Hisham Guo, Hao Stover, Daniel G. Ekram, Muhammad B. Peluffo, Guillermo 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 P. Letai, Antony Barry, William T. Carroll, Jason S. Long, Henry W. Brown, Myles Liu, X. Shirley Meyer, Clifford A. Polyak, Kornelia Bradner, James |
| author2 | Broad Institute of MIT and Harvard |
| author_facet | Broad Institute of MIT and Harvard Shu, Shaokun Lin, Charles Y. He, Housheng Hansen Witwicki, Robert M. Tabassum, Doris P. Roberts, Justin M. Janiszewska, Michalina Jin Huh, Sung Liang, Yi Ryan, Jeremy Doherty, Ernest Mohammed, Hisham Guo, Hao Stover, Daniel G. Ekram, Muhammad B. Peluffo, Guillermo 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 P. Letai, Antony Barry, William T. Carroll, Jason S. Long, Henry W. Brown, Myles Liu, X. Shirley Meyer, Clifford A. Polyak, Kornelia Bradner, James |
| author_sort | Shu, Shaokun |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T13:41:24Z |
| format | Article |
| id | mit-1721.1/109131 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:41:24Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1091312022-09-28T15:32:27Z 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 Jin Huh, Sung Liang, Yi Ryan, Jeremy Doherty, Ernest Mohammed, Hisham Guo, Hao Stover, Daniel G. Ekram, Muhammad B. Peluffo, Guillermo 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 P. Letai, Antony Barry, William T. Carroll, Jason S. Long, Henry W. Brown, Myles Liu, X. Shirley Meyer, Clifford A. Polyak, Kornelia Bradner, James Broad Institute of MIT and Harvard Bradner, James 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. 2017-05-16T19:21:55Z 2017-05-16T19:21:55Z 2016-01 2014-11 Article http://purl.org/eprint/type/JournalArticle 0028-0836 1476-4687 http://hdl.handle.net/1721.1/109131 Shu, Shaokun; Lin, Charles Y.; He, Housheng Hansen; Witwicki, Robert M.; Tabassum, Doris P.; Roberts, Justin M.; Janiszewska, Michalina, et al. “Response and Resistance to BET Bromodomain Inhibitors in Triple-Negative Breast Cancer.” Nature 529, no. 7586 (January 2016): 413–417. © 2016 Macmillan Publishers Limited, part of Springer Nature en_US http://dx.doi.org/10.1038/nature16508 Nature Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Nature Publishing Group PMC |
| spellingShingle | Shu, Shaokun Lin, Charles Y. He, Housheng Hansen Witwicki, Robert M. Tabassum, Doris P. Roberts, Justin M. Janiszewska, Michalina Jin Huh, Sung Liang, Yi Ryan, Jeremy Doherty, Ernest Mohammed, Hisham Guo, Hao Stover, Daniel G. Ekram, Muhammad B. Peluffo, Guillermo 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 P. Letai, Antony Barry, William T. Carroll, Jason S. Long, Henry W. Brown, Myles Liu, X. Shirley Meyer, Clifford A. Polyak, Kornelia Bradner, James 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 |
| url | http://hdl.handle.net/1721.1/109131 |
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