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Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor.

Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor.

Authors :
Barber, Louise J
Sandhu, Shahneen
Chen, Lina
Campbell, James
Kozarewa, Iwanka
Fenwick, Kerry
Assiotis, Ioannis
Rodrigues, Daniel Nava
Reis-Filho, Jorge S
Moreno, Victor
Mateo, Joaquin
Molife, L Rhoda
De Bono, Johann
Kaye, Stan
Lord, Christopher J
Ashworth, Alan
Source :
Journal of Pathology; Feb2013, Vol. 229 Issue 3, p422-429, 8p
Publication Year :
2013

Abstract

PARP inhibitors ( PARPi) for the treatment of BRCA1 or BRCA2 deficient tumours are currently the focus of seminal clinical trials exploiting the concept of synthetic lethality. Although clinical resistance to PARPi has been described, the mechanism underlying this has not been elucidated. Here, we investigate tumour material from patients who had developed resistance to the PARPi olaparib, subsequent to showing an initial clinical response. Massively parallel DNA sequencing of treatment-naive and post-olaparib treatment biopsies identified tumour-specific BRCA2 secondary mutations in olaparib-resistant metastases. These secondary mutations restored full-length BRCA2 protein, and most likely cause olaparib resistance by re-establishing BRCA2 function in the tumour cells. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00223417
Volume :
229
Issue :
3
Database :
Complementary Index
Journal :
Journal of Pathology
Publication Type :
Academic Journal
Accession number :
85101729
Full Text :
https://doi.org/10.1002/path.4140