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Stabilization of mutant BRCA1 protein confers PARP inhibitor and platinum resistance

Neil Johnson1, Shawn F Johnson, Wei Yao

  • 1Departments of Medical Oncology, Radiation Oncology, and Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215.

Proceedings of the National Academy of Sciences of the United States of America
|October 3, 2013
PubMed

Insights

Tumors with BRCA1 mutations develop resistance to PARP inhibitors and platinum drugs. HSP90 stabilizes mutant BRCA1, conferring resistance, but HSP90 inhibition restores sensitivity.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • BRCA1 deficiency impairs DNA repair, making cells sensitive to PARP inhibitors.
  • Acquired resistance limits the clinical effectiveness of PARP inhibitors in BRCA1-mutant cancers.
  • Mutations in the BRCA1 C-terminal (BRCT) domain often lead to protein degradation.

Purpose of the Study:

  • To investigate the mechanisms of acquired resistance to PARP inhibitors in BRCA1-deficient cells.
  • To explore the role of HSP90 in stabilizing mutant BRCA1 and conferring resistance.
  • To identify potential therapeutic strategies to overcome resistance.

Main Methods:

  • Utilized cell culture models of BRCA1-deficient cancers.
  • Investigated the effect of PARP inhibitor selection pressure on BRCA1 protein stability.
  • Assessed the interaction of stabilized mutant BRCA1 with DNA repair proteins.
  • Tested the efficacy of HSP90 inhibitors in restoring sensitivity to PARP inhibitors.
  • Analyzed clinical samples for BRCA1 and 53BP1 protein expression.

Main Results:

  • HSP90 stabilizes a mutant BRCA1 protein under PARP inhibitor selection.
  • Stabilized mutant BRCA1 restores DNA repair capacity and confers resistance to PARP inhibitors and cisplatin.
  • HSP90 inhibition resensitizes resistant cells to PARP inhibitors.
  • Acquired TP53BP1 mutations facilitate DNA end resection in resistant cells.
  • Clinical samples show increased mutant BRCA1 and decreased 53BP1 in resistant ovarian cancers.

Conclusions:

  • HSP90-mediated stabilization of mutant BRCA1 is a key mechanism of acquired resistance.
  • A two-event mechanism involving mutant BRCA1 stabilization and TP53BP1 mutation drives resistance.
  • Targeting HSP90 offers a potential strategy to re-sensitize BRCA1-mutant tumors to therapy.
Keywords:
cancer therapyhomologous recombination

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