Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer | Zendy

Alison Kurimchak | Zendy; Claude Shelton | Zendy; Kelly Duncan | Zendy; Katherine J. Johnson | Zendy; Jennifer Brown | Zendy; Shane W. O’Brien | Zendy; Rashid Gabbasov | Zendy; Lauren S. Fink | Zendy; Yuesheng Li | Zendy; Nicole Lounsbury | Zendy; Magid AbouGharbia | Zendy; Wayne E. Childers | Zendy; Denise C. Connolly | Zendy; Jonathan Chernoff | Zendy; Jeffrey R. Peterson | Zendy; James S. Duncan | Zendy

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Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer

Author(s) -

Alison Kurimchak,

Claude Shelton,

Kelly Duncan,

Katherine J. Johnson,

Jennifer Brown,

Shane W. O’Brien,

Rashid Gabbasov,

Lauren S. Fink,

Yuesheng Li,

Nicole Lounsbury,

Magid AbouGharbia,

Wayne E. Childers,

Denise C. Connolly,

Jonathan Chernoff,

Jeffrey R. Peterson,

James S. Duncan

Publication year - 2016

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2016.06.091

Subject(s) - kinome , bromodomain , reprogramming , brd4 , olaparib , kinase , cancer research , drug resistance , biology , pharmacology , chemistry , microbiology and biotechnology , cell , epigenetics , biochemistry , genetics , enzyme , gene , polymerase , poly adp ribose polymerase

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.

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