title: Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer.
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.
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Kurimchak
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Claude
authors.initials: C
authors.lastname: Shelton
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Duncan
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Johnson
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Brown
authors.affiliation: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Shane
authors.initials: S
authors.lastname: O'Brien
authors.affiliation: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Department of Genetics, Kazan (Volga Region) Federal University, Kazan 420008, Russia.
authors.forename: Rashid
authors.initials: R
authors.lastname: Gabbasov
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Lauren S
authors.initials: LS
authors.lastname: Fink
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Li
authors.affiliation: Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Lounsbury
authors.affiliation: Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
authors.forename: Magid
authors.initials: M
authors.lastname: Abou-Gharbia
authors.affiliation: Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
authors.forename: Wayne E
authors.initials: WE
authors.lastname: Childers
authors.affiliation: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Denise C
authors.initials: DC
authors.lastname: Connolly
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chernoff
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Peterson
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Electronic address: james.duncan2@fccc.edu.
authors.forename: James S
authors.initials: JS
authors.lastname: Duncan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D005260:Female; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011506:Proteins; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C000624329:bromodomain and extra-terminal domain protein, human