BRCA1/2 mutations and poly (ADP-ribose) polymerase (PARP) inhibitors are paradigmatic of synthetic lethal therapy. However, the activity of PARP inhibitors seems to vary considerably across BRCA1/2-mutant cancers and new insights into the tumour-lineage dependency of this synthetic lethal relationship might explain why BRCA1/2 mutations are not tumour-agnostic biomarkers of a response to PARP inhibitors.
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N.J.C. has received research funding from Aguoron Pharmaceuticals and Pfizer for the development of rucaparib, from BioMarin for studies of talazoparib and from Tesaro for studies of niraparib. N.J.C. has also been paid by Abbvie for consultancy relating to the development of veliparib. N.J.C. is an inventor on the patent relating to the use of rucaparib in homologous recombination repair-deficient cancer, and Newcastle University receives royalty income from the sales of rucaparib that are shared with contributors to its development, including N.J.C. and Y.D. Y.D. has received research grant funding from AstraZeneca, Clovis Oncology and Tesaro and has participated in scientific advisory boards for AstraZeneca, Clovis Oncology, Merck and Tesaro. Y.D. is also a principal investigator of clinical trials of olaparib and rucaparib. S.S.-S. declares no competing interests.
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Curtin, N.J., Drew, Y. & Sharma-Saha, S. Why BRCA mutations are not tumour-agnostic biomarkers for PARP inhibitor therapy. Nat Rev Clin Oncol (2019) doi:10.1038/s41571-019-0285-2