title: Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers.
abstract: 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.
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
authors.forename: Wataru
authors.initials: W
authors.lastname: Sakai
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Swisher
authors.forename: Beth Y
authors.initials: BY
authors.lastname: Karlan
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Agarwal
authors.forename: Jake
authors.initials: J
authors.lastname: Higgins
authors.forename: Cynthia
authors.initials: C
authors.lastname: Friedman
authors.forename: Emily
authors.initials: E
authors.lastname: Villegas
authors.forename: Céline
authors.initials: C
authors.lastname: Jacquemont
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Farrugia
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.forename: Nicole
authors.initials: N
authors.lastname: Urban
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Taniguchi
mesh_terms: D052176:Azulenes / Q000494:pharmacology; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D001569:Benzodiazepines / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics*; D005260:Female; D024522:Genes, BRCA2; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
chemical_list: C479234:1-(4-dimethylaminomethylphenyl)-8,9-dihydro-7H-2,7,9a-benzo(cd)azulen-6-one; D052176:Azulenes; D024682:BRCA2 Protein; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D001569:Benzodiazepines; D002945:Cisplatin