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Cell Rep. 2016 Aug 2;16(5):1273-1286. doi: 10.1016/j.celrep.2016.06.091. Epub 2016 Jul 21.

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

Author information

1
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
2
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
3
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Department of Genetics, Kazan (Volga Region) Federal University, Kazan 420008, Russia.
4
Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
5
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Electronic address: james.duncan2@fccc.edu.

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.

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PMID:
27452461
PMCID:
PMC4972668
DOI:
10.1016/j.celrep.2016.06.091
[Indexed for MEDLINE]
Free PMC Article

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