PLX156821

GSE82329: Adaptation of the Kinome Promotes Resistance to BET Bromodomain Inhibitors in Ovarian Cancer

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Small molecule BET bromodomain inhibitors (BETi) are actively being pursued in clinical trials for the treatment of a variety of cancers, however, the mechanisms of resistance to targeted BET protein inhibitors remain poorly understood. Using a novel mass spectrometry approach that globally measures kinase signaling at the proteomic level, we evaluated the response of the kinome to targeted BET inhibitor 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 BET inhibitor therapy. SOURCE: yuesheng Li (yue-sheng.li@fccc.edu) - Fox Chase Cancer Center