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

Sakai, Wataru and Swisher, Elizabeth M. and Karlan, Beth Y. and Agarwal, Mukesh K. and Higgins, Jake and Friedman, Cynthia and Villegas, Emily and Jacquemont, Céline and Farrugia, Daniel J. and Couch, Fergus J. and Urban, Nicole and Taniguchi, Toshiyasu (2008) Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature, 451 (7182). pp. 1116-1120. ISSN 1476-4687

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Ovarian carcinomas with mutations in the tumour suppressor BRCA2 are particularly sensitive to platinum compounds. However, such carcinomas ultimately develop cisplatin resistance. The mechanism of that resistance is largely unknown. Here we show that acquired resistance to cisplatin can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. First, in a cisplatin-resistant BRCA2-mutated breast-cancer cell line, HCC1428, a secondary genetic change in BRCA2 rescued BRCA2 function. Second, cisplatin selection of a BRCA2-mutated pancreatic cancer cell line, Capan-1 (refs 3, 4), led to five different secondary mutations that restored the wild-type BRCA2 reading frame. All clones with secondary mutations were resistant both to cisplatin and to a poly(ADP-ribose) polymerase (PARP) inhibitor (AG14361). Finally, we evaluated recurrent cancers from patients whose primary BRCA2-mutated ovarian carcinomas were treated with cisplatin. The recurrent tumour that acquired cisplatin resistance had undergone reversion of its BRCA2 mutation. Our results suggest that secondary mutations that restore the wild-type BRCA2 reading frame may be a major clinical mediator of acquired resistance to platinum-based chemotherapy.

Item Type: Article or Abstract
Additional Information: This article is available to subscribers only via the URL above
DOI: 10.1038/nature06633
PubMed ID: 18264087
PMCID: PMC2577037
Grant Numbers: R01 CA125636-02, K08 CA096610-01, P50 CA083636-10
Keywords or MeSH Headings: Azulenes/pharmacology; BRCA2 Protein/genetics/metabolism; Benzodiazepines/pharmacology; Breast Neoplasms/drug therapy/genetics/pathology; Cell Line, Tumor; Cisplatin/*pharmacology; Drug Resistance, Neoplasm/*drug effects/*genetics; Female; *Genes, BRCA2; Humans; Middle Aged; Mutation/*genetics; Neoplasms/*drug therapy/*genetics; Ovarian Neoplasms/drug therapy/genetics; Pancreatic Neoplasms/drug therapy/genetics/pathology; Poly(ADP-ribose) Polymerases/antagonists & inhibitors;
Subjects: Cellular and Organismal Processes > Genetic processes > Mutation
Diseases > Solid tumors > Ovarian cancer
Therapeutics > Drug Therapy
Depositing User: authors@FHCRC Administrator-Import
Date Deposited: 03 Oct 2008 21:21
Last Modified: 14 Feb 2012 14:42

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