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. 2013 Feb;229(3):422-9.
doi: 10.1002/path.4140.

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

Louise J Barber  1 , Shahneen Sandhu, Lina Chen, James Campbell, Iwanka Kozarewa, Kerry Fenwick, Ioannis Assiotis, Daniel Nava Rodrigues, Jorge S Reis Filho, Victor Moreno, Joaquin Mateo, L Rhoda Molife, Johann De Bono, Stan Kaye, Christopher J Lord, Alan Ashworth
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Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor

Louise J Barber et al. J Pathol. 2013 Feb.

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 VSports手机版. 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. .

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