Homologous repair deficiency and PARP inhibitors in cancer management

DNA damage acquired due to several reasons such as ionizing radiation, reactive oxygen species, and replication errors can be repaired by various mechanisms. Double-stranded breaks are mostly repaired by the homologous recombination repair (HRR) pathway, which is an error-free repair mechanism. Mutations in BRCA1/2 and other genes, such as Rad51B/C/D, PALB2, ATM, CHK1/2, and CDK12, and Fanconi anemia genes are found associated with HR deficiency. Tumors displaying a deficient HR repair pathway are termed as homologous recombination deficient (HRD). In such tumors, alternate DNA repair pathways exist, requiring poly-ADP ribose polymerase (PARP) as the key effector protein. Precision targeting of such tumors using PARP inhibitors has shown significant benefits in the clinic for several cancers including ovarian and breast cancers. However, current challenges of identifying a cost-effective biomarker for HRD and acquired resistance to PARP inhibitors need to be addressed for these to become the mainstay therapy for HRD tumors.