Journal article
The MAPK pathway regulates intrinsic resistance to BET inhibitors in colorectal cancer.
- Abstract:
- The bromodomain and extra-terminal domain (BET) family proteins are epigenetic readers for acetylated histone marks. Emerging BET bromodomain inhibitors have exhibited antineoplastic activities in a wide range of human cancers through suppression of oncogenic transcription factors, including MYC. However, the preclinical activities of BET inhibitors in advanced solid cancers are moderate at best. To improve BET-targeted therapy, we interrogated mechanisms mediating resistance to BET inhibitors in colorectal cancer (CRC).Using a panel of molecularly defined CRC cell lines, we examined the impact of BET inhibition on cellular proliferation and survival as well as MYC activity. We further tested the ability of inhibitors targeting the RAF/MEK/ERK (MAPK) pathway to enhance MYC suppression and circumvent intrinsic resistance to BET inhibitors. Key findings were validated using genetic approaches.BET inhibitors as monotherapy moderately reduced CRC cell proliferation and MYC expression. Blockade of the MAPK pathway synergistically sensitized CRC cells to BET inhibitors, leading to potent apoptosis and MYC downregulation in vitro and in vivo. A combination of JQ1 and trametinib, but neither agent alone, induced significant regression of subcutaneous CRC xenografts. ` Conclusions: Our findings suggest that the MAPK pathway confers intrinsic resistance to BET inhibitors in CRC and propose an effective combination strategy for the treatment of CRC.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
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(Preview, Accepted manuscript, pdf, 2.4MB, Terms of use)
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- Publisher copy:
- 10.1158/1078-0432.CCR-16-0453
Authors
- Publisher:
- American Association for Cancer Research
- Journal:
- Clinical Cancer Research More from this journal
- Volume:
- 23
- Issue:
- 8
- Pages:
- 2027-2037
- Publication date:
- 2016-09-27
- Acceptance date:
- 2016-09-14
- DOI:
- ISSN:
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1078-0432 and 1557-3265
- Pmid:
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27678457
- Language:
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English
- Keywords:
- Pubs id:
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pubs:648037
- UUID:
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uuid:43a93e60-cbfe-4b80-b613-40450f0f3b7c
- Local pid:
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pubs:648037
- Source identifiers:
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648037
- Deposit date:
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2016-11-11
Terms of use
- Copyright holder:
- American Association for Cancer Research
- Copyright date:
- 2016
- Notes:
- Copyright © 2016, American Association for Cancer Research.
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