CRISPR/Cas9induced saturated mutagenesis identifies Rad51 haplotype as a marker of PARP inhibitor sensitivity in breast cancer

Abstract

Breast cancer treatment with poly(adPribose)poly merase (ParP) inhibitors is currently limited to cells defective in the homologous recombination repair (Hrr) pathway. The chemical inhibition of many HRR deficiency genes may sensi tize cancer cells to ParP inhibitors. in the present study, Rad51, a central player in the Hrr pathway, was selected to explore additional low variation and highly representative markers for ParP inhibitor activity. a criSPr/cas9based saturated mutation approach for the Rad51 WalKer domain was used to evaluate the sensitivity of the ParP inhibitor olaparib. Five amino acid mutation sites were identified in olaparibresistant cells. Two Rad51 haplotypes were assembled from the muta tions, and may represent useful pharmacogenomic markers of ParP inhibitor sensitivity.