| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 2041199 | Cell Reports | 2016 | 14 Pages |
•Inhibition of BET proteins reprograms kinome activity in ovarian cancer cells•Receptor tyrosine kinase activation overcomes BET inhibition, causing resistance•Elevated PI3K/ERK activity stabilizes MYC/FOSL1 proteins in JQ1-resistant cells•Co-targeting BET proteins and RTK or PI3K signaling enhances BET inhibitor therapy
SummarySmall-molecule BET bromodomain inhibitors (BETis) are actively being pursued in clinical trials for the treatment of a variety of cancers, but the mechanisms of resistance to BETis remain poorly understood. Using a mass spectrometry approach that globally measures kinase signaling at the proteomic level, we evaluated the response of the kinome to targeted BETi treatment in a panel of BRD4-dependent ovarian carcinoma (OC) cell lines. Despite initial inhibitory effects of BETi, OC cells acquired resistance following sustained treatment with the BETi JQ1. Through application of multiplexed inhibitor beads (MIBs) and mass spectrometry, we demonstrate that BETi resistance is mediated by adaptive kinome reprogramming, where activation of compensatory pro-survival kinase networks overcomes BET protein inhibition. Furthermore, drug combinations blocking these kinases may prevent or delay the development of drug resistance and enhance the efficacy of BETi therapy.
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