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Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor
Author(s) -
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
Publication year - 2013
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4140
Subject(s) - olaparib , synthetic lethality , parp inhibitor , poly adp ribose polymerase , cancer research , mutation , medicine , biology , dna repair , genetics , dna , gene , polymerase
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.