Publication Date:
2008-02-12
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2577037/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2577037/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sakai, Wataru -- Swisher, Elizabeth M -- Karlan, Beth Y -- Agarwal, Mukesh K -- Higgins, Jake -- Friedman, Cynthia -- Villegas, Emily -- Jacquemont, Celine -- Farrugia, Daniel J -- Couch, Fergus J -- Urban, Nicole -- Taniguchi, Toshiyasu -- K08 CA096610/CA/NCI NIH HHS/ -- K08 CA096610-01/CA/NCI NIH HHS/ -- P50 CA083636/CA/NCI NIH HHS/ -- P50 CA083636-10/CA/NCI NIH HHS/ -- R01 CA125636/CA/NCI NIH HHS/ -- R01 CA125636-02/CA/NCI NIH HHS/ -- England -- Nature. 2008 Feb 28;451(7182):1116-20. doi: 10.1038/nature06633. Epub 2008 Feb 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18264087" target="_blank"〉PubMed〈/a〉
Keywords:
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) Polymerase Inhibitors
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink
