Stabilization of mutant BRCA1 protein confers PARP inhibitor and platinum resistance

Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):17041-6. doi: 10.1073/pnas.1305170110. Epub 2013 Oct 1.

Abstract

Breast Cancer Type 1 Susceptibility Protein (BRCA1)-deficient cells have compromised DNA repair and are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. Despite initial responses, the development of resistance limits clinical efficacy. Mutations in the BRCA C-terminal (BRCT) domain of BRCA1 frequently create protein products unable to fold that are subject to protease-mediated degradation. Here, we show HSP90-mediated stabilization of a BRCT domain mutant BRCA1 protein under PARP inhibitor selection pressure. The stabilized mutant BRCA1 protein interacted with PALB2-BRCA2-RAD51, was essential for RAD51 focus formation, and conferred PARP inhibitor as well as cisplatin resistance. Treatment of resistant cells with the HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin reduced mutant BRCA1 protein levels and restored their sensitivity to PARP inhibition. Resistant cells also acquired a TP53BP1 mutation that facilitated DNA end resection in the absence of a BRCA1 protein capable of binding CtIP. Finally, concomitant increased mutant BRCA1 and decreased 53BP1 protein expression occur in clinical samples of BRCA1-mutated recurrent ovarian carcinomas that have developed resistance to platinum. These results provide evidence for a two-event mechanism by which BRCA1-mutant tumors acquire anticancer therapy resistance.

Keywords: cancer therapy; homologous recombination.

Publication types

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

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism*
  • BRCA2 Protein / genetics
  • BRCA2 Protein / metabolism
  • Benzoquinones / pharmacology
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Fanconi Anemia Complementation Group N Protein
  • Female
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Lactams, Macrocyclic / pharmacology
  • Mutation*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Platinum / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein Structure, Tertiary
  • Rad51 Recombinase / genetics
  • Rad51 Recombinase / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Antineoplastic Agents
  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • Benzoquinones
  • Fanconi Anemia Complementation Group N Protein
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Nuclear Proteins
  • PALB2 protein, human
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Tumor Suppressor Proteins
  • 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
  • Platinum
  • Poly(ADP-ribose) Polymerases
  • RAD51 protein, human
  • Rad51 Recombinase
  • Cisplatin