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Kurimchak AM , Shelton C , Duncan KE , Johnson KJ , Brown J , O'Brien S , Gabbasov R , Fink LS , Li Y , Lounsbury N , Abou-Gharbia M , Childers WE , Connolly DC , Chernoff J , Peterson JR , Duncan JS
Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer
Cell Rep. 2016 Aug 2;16(5) :1273-86
PMID: 27452461 PMCID: PMC4972668
AbstractSmall-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.
NotesKurimchak, Alison M Shelton, Claude Duncan, Kelly E Johnson, Katherine J Brown, Jennifer O'Brien, Shane Gabbasov, Rashid Fink, Lauren S Li, Yuesheng Lounsbury, Nicole Abou-Gharbia, Magid Childers, Wayne E Connolly, Denise C Chernoff, Jonathan Peterson, Jeffrey R Duncan, James S R01 CA142928/CA/NCI NIH HHS/United States R01 GM083025/GM/NIGMS NIH HHS/United States United States Cell Rep. 2016 Aug 2;16(5):1273-86. doi: 10.1016/j.celrep.2016.06.091. Epub 2016 Jul 21.