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Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66. doi: 10.1073/pnas.1608319113. Epub 2016 Jul 18.

Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β-dependent mechanisms.

Author information

1
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520;
2
Gilead Sciences, Foster City, CA 94404;
3
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520; joseph.schlessinger@yale.edu ben.turk@yale.edu david.calderwood@yale.edu.
4
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520; Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520 joseph.schlessinger@yale.edu ben.turk@yale.edu david.calderwood@yale.edu.

Abstract

Bromodomain and extraterminal domain protein inhibitors (BETi) hold great promise as a novel class of cancer therapeutics. Because acquired resistance typically limits durable responses to targeted therapies, it is important to understand mechanisms by which tumor cells adapt to BETi. Here, through pooled shRNA screening of colorectal cancer cells, we identified tripartite motif-containing protein 33 (TRIM33) as a factor promoting sensitivity to BETi. We demonstrate that loss of TRIM33 reprograms cancer cells to a more resistant state through at least two mechanisms. TRIM33 silencing attenuates down-regulation of MYC in response to BETi. Moreover, loss of TRIM33 enhances TGF-β receptor expression and signaling, and blocking TGF-β receptor activity potentiates the antiproliferative effect of BETi. These results describe a mechanism for BETi resistance and suggest that combining inhibition of TGF-β signaling with BET bromodomain inhibition may offer new therapeutic benefits.

KEYWORDS:

JQ1; TGF-β; TRIM33; bromodomain inhibitor; drug resistance

PMID:
27432991
PMCID:
PMC4978292
DOI:
10.1073/pnas.1608319113
[Indexed for MEDLINE]
Free PMC Article

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