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

Xiarong Shi, Valia T. Mihaylova, Leena Kuruvilla, Fang Chen, Stephen Viviano, Massimiliano Baldassarre, David Sperandio, Ruben Martinez, Peng Yue, Jamie G. Bates, David G. Breckenridge, Joseph Schlessinger, Benjamin E. Turk, David A. Calderwood

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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.

Original languageEnglish
Pages (from-to)E4558-4566
Number of pages9
JournalPNAS
Volume113
Issue number31
Early online date18 Jul 2016
DOIs
Publication statusPublished - 2 Aug 2016

Keywords

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

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    Shi, X., Mihaylova, V. T., Kuruvilla, L., Chen, F., Viviano, S., Baldassarre, M., Sperandio, D., Martinez, R., Yue, P., Bates, J. G., Breckenridge, D. G., Schlessinger, J., Turk, B. E., & Calderwood, D. A. (2016). Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β-dependent mechanisms. PNAS, 113(31), E4558-4566. https://doi.org/10.1073/pnas.1608319113