1. Division of Human Biology,
2. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA
3. Department of Obstetrics and Gynecology,
4. Department of Medicine, University of Washington, Seattle, Washington 98195-7720, USA
5. Cedars-Sinai Medical Center, Women's Cancer Research Institute, Los Angeles, California 90048-1865, USA
6. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA
7. Department of Genome Sciences, University of Washington, Seattle, Washington 98195-7720, USA

Correspondence to: Toshiyasu Taniguchi^1,2 Correspondence and requests for materials should be addressed to T.T. (Email: ttaniguc@fhcrc.org).

Abstract

Ovarian carcinomas with mutations in the tumour suppressor BRCA2 are particularly sensitive to platinum compounds¹. However, such carcinomas ultimately develop cisplatin resistance. The mechanism of that resistance is largely unknown². 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.

1. Division of Human Biology,
2. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA
3. Department of Obstetrics and Gynecology,
4. Department of Medicine, University of Washington, Seattle, Washington 98195-7720, USA
5. Cedars-Sinai Medical Center, Women's Cancer Research Institute, Los Angeles, California 90048-1865, USA
6. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA
7. Department of Genome Sciences, University of Washington, Seattle, Washington 98195-7720, USA

Correspondence to: Toshiyasu Taniguchi^1,2 Correspondence and requests for materials should be addressed to T.T. (Email: ttaniguc@fhcrc.org).

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