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Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers

Wataru Sakai1, Elizabeth M Swisher, Beth Y Karlan

  • 1Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.

Nature
|February 12, 2008
PubMed

Insights

Secondary mutations in BRCA2 can cause resistance to cisplatin chemotherapy in BRCA2-mutated cancers. These BRCA2 gene mutations restore normal function, leading to resistance against platinum drugs and PARP inhibitors.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • BRCA2 mutations confer sensitivity to platinum-based chemotherapy in ovarian carcinomas.
  • Acquired resistance to cisplatin is a significant clinical challenge in these cancers.
  • The molecular mechanisms underlying cisplatin resistance in BRCA2-mutated cancers remain largely unknown.

Purpose of the Study:

  • To investigate the mechanisms of acquired cisplatin resistance in BRCA2-mutated cancers.
  • To identify genetic alterations that mediate resistance to platinum compounds.

Main Methods:

  • Utilized cisplatin-resistant BRCA2-mutated breast and pancreatic cancer cell lines (HCC1428, Capan-1).
  • Applied cisplatin selection to induce resistance and analyzed secondary mutations in BRCA2.
  • Evaluated resistance to cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitor AG14361.
  • Examined recurrent ovarian tumors from patients treated with cisplatin.

Main Results:

  • Identified secondary intragenic BRCA2 mutations that restore the wild-type reading frame and BRCA2 function.
  • Demonstrated that these secondary mutations confer resistance to both cisplatin and PARP inhibitors.
  • Observed reversion of BRCA2 mutations in recurrent cisplatin-resistant ovarian tumors from patients.

Conclusions:

  • Secondary mutations restoring the BRCA2 reading frame are a key mechanism of acquired cisplatin resistance.
  • This mechanism contributes to clinical resistance to platinum-based chemotherapy in BRCA2-mutated cancers.
  • Understanding this resistance pathway may inform future therapeutic strategies.

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