| Literature DB >> 27452461 |
Alison M Kurimchak1, Claude Shelton1, Kelly E Duncan1, Katherine J Johnson1, Jennifer Brown1, Shane O'Brien2, Rashid Gabbasov3, Lauren S Fink1, Yuesheng Li1, Nicole Lounsbury4, Magid Abou-Gharbia4, Wayne E Childers4, Denise C Connolly2, Jonathan Chernoff1, Jeffrey R Peterson1, James S Duncan5.
Abstract
Small-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.Entities:
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Year: 2016 PMID： 27452461 PMCID： PMC4972668 DOI： 10.1016/j.celrep.2016.06.091
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423