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

Wataru Sakai, Elizabeth M. Swisher, Beth Y. Karlan, Mukesh K. Agarwal, Jake Higgins, Cynthia Friedman, Emily Villegas, Céline Jacquemont, Daniel J. Farrugia, Fergus J Couch, Nicole Urban, Toshiyasu Taniguchi

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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.

Original languageEnglish (US)
Pages (from-to)1116-1120
Number of pages5
JournalNature
Volume451
Issue number7182
DOIs
StatePublished - Feb 28 2008

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Cisplatin
Mutation
Reading Frames
Neoplasms
Carcinoma
Platinum Compounds
Cell Line
Platinum
Pancreatic Neoplasms
Clone Cells
Breast Neoplasms
Drug Therapy

ASJC Scopus subject areas

  • General

Cite this

Sakai, W., Swisher, E. M., Karlan, B. Y., Agarwal, M. K., Higgins, J., Friedman, C., ... Taniguchi, T. (2008). Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature, 451(7182), 1116-1120. https://doi.org/10.1038/nature06633

Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. / Sakai, Wataru; Swisher, Elizabeth M.; Karlan, Beth Y.; Agarwal, Mukesh K.; Higgins, Jake; Friedman, Cynthia; Villegas, Emily; Jacquemont, Céline; Farrugia, Daniel J.; Couch, Fergus J; Urban, Nicole; Taniguchi, Toshiyasu.

In: Nature, Vol. 451, No. 7182, 28.02.2008, p. 1116-1120.

Research output: Contribution to journalArticle

Sakai, W, Swisher, EM, Karlan, BY, Agarwal, MK, Higgins, J, Friedman, C, Villegas, E, Jacquemont, C, Farrugia, DJ, Couch, FJ, Urban, N & Taniguchi, T 2008, 'Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers', Nature, vol. 451, no. 7182, pp. 1116-1120. https://doi.org/10.1038/nature06633
Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J, Friedman C et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature. 2008 Feb 28;451(7182):1116-1120. https://doi.org/10.1038/nature06633
Sakai, Wataru ; Swisher, Elizabeth M. ; Karlan, Beth Y. ; Agarwal, Mukesh K. ; Higgins, Jake ; Friedman, Cynthia ; Villegas, Emily ; Jacquemont, Céline ; Farrugia, Daniel J. ; Couch, Fergus J ; Urban, Nicole ; Taniguchi, Toshiyasu. / Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. In: Nature. 2008 ; Vol. 451, No. 7182. pp. 1116-1120.
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