Platinum and PARP Inhibitor Resistance Due to Overexpression of MicroRNA-622 in BRCA1-Mutant Ovarian Cancer

Cell Rep. 2016 Jan 26;14(3):429-439. doi: 10.1016/j.celrep.2015.12.046. Epub 2016 Jan 7.


High-grade serous ovarian carcinomas (HGSOCs) with BRCA1/2 mutations exhibit improved outcome and sensitivity to double-strand DNA break (DSB)-inducing agents (i.e., platinum and poly(ADP-ribose) polymerase inhibitors [PARPis]) due to an underlying defect in homologous recombination (HR). However, resistance to platinum and PARPis represents a significant barrier to the long-term survival of these patients. Although BRCA1/2-reversion mutations are a clinically validated resistance mechanism, they account for less than half of platinum-resistant BRCA1/2-mutated HGSOCs. We uncover a resistance mechanism by which a microRNA, miR-622, induces resistance to PARPis and platinum in BRCA1 mutant HGSOCs by targeting the Ku complex and restoring HR-mediated DSB repair. Physiologically, miR-622 inversely correlates with Ku expression during the cell cycle, suppressing non-homologous end-joining and facilitating HR-mediated DSB repair in S phase. Importantly, high expression of miR-622 in BRCA1-deficient HGSOCs is associated with worse outcome after platinum chemotherapy, indicating microRNA-mediated resistance through HR rescue.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, Nuclear / genetics
  • Antigens, Nuclear / metabolism
  • Antineoplastic Agents / pharmacology*
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism*
  • Base Sequence
  • Cell Line, Tumor
  • DNA End-Joining Repair / drug effects
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Disease-Free Survival
  • Female
  • Homologous Recombination / drug effects
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Ku Autoantigen
  • Mice
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Oligonucleotides, Antisense / metabolism
  • Organoplatinum Compounds / pharmacology*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / mortality
  • Ovarian Neoplasms / pathology
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • RNA Interference
  • Sequence Alignment
  • Tumor Suppressor p53-Binding Protein 1


  • Antigens, Nuclear
  • Antineoplastic Agents
  • BRCA1 Protein
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • MicroRNAs
  • Oligonucleotides, Antisense
  • Organoplatinum Compounds
  • Poly(ADP-ribose) Polymerase Inhibitors
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • Xrcc6 protein, human
  • Xrcc6 protein, mouse
  • Ku Autoantigen