title: Ovarian cancer-associated mutations disable catalytic activity of CDK12, a kinase that promotes homologous recombination repair and resistance to cisplatin and poly(ADP-ribose) polymerase inhibitors.
abstract: Mutations in the tumor suppressors BRCA1 and BRCA2, which encode proteins that are key participants in homologous recombination (HR) repair, occur in ∼20% of high grade serous ovarian cancers. Although only 20% of these tumors have mutations in BRCA1 and BRCA2, nearly 50% of these tumors have defects in HR. Notably, however, the underlying genetic defects that give rise to HR defects in the absence of BRCA1 and BRCA2 mutations have not been fully elucidated. Here we show that the recurrent somatic CDK12 mutations identified in ovarian cancers impair the catalytic activity of this kinase, which is involved in the transcription of a subset of genes, including BRCA1 and other DNA repair genes. Furthermore, we show that disabling CDK12 function in ovarian cancer cells reduces BRCA1 levels, disrupts HR repair, and sensitizes these cells to the cross-linking agents melphalan and cisplatin and to the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888). Taken together, these findings suggest that many CDK12 mutations are an unrecognized cause of HR defects in ovarian cancers.
authors.affiliation: From the Department of Molecular Pharmacology and Experimental Therapeutics and.
authors.forename: Poorval M
authors.initials: PM
authors.lastname: Joshi
authors.forename: Shari L
authors.initials: SL
authors.lastname: Sutor
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Huntoon
authors.forename: Larry M
authors.initials: LM
authors.lastname: Karnitz
mesh_terms: D055162:Biocatalysis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000494:pharmacology; D018844:Cyclin-Dependent Kinases / Q000172:deficiency / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D059765:Homologous Recombination / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
chemical_list: D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C447339:CDK12 protein, human; D018844:Cyclin-Dependent Kinases; D002945:Cisplatin
keywords: BRCA1; CDK (Cyclin-dependent Kinase); CDK12; Cisplatin; DNA Damage; Homologous Recombination; Ovarian Cancer; Poly(ADP)-ribose Polymerase; RAD51; Veliparib