CRISPR-Cas9-based functional analysis of PARP inhibitor response in BRCA-mutated breast cancer and its implications for precision pharmacogenomics

BRCA1 and BRCA2 are tumour suppressor genes that play an essential role in homologous recombination and repair damaged DNA, maintaining genomic stability. Mutations in these genes can lead to inaccurate DNA repair, increasing the risk of breast cancer, and can be effectively targeted by PARP inhibitors. This review summarises the role of CRISPR-Cas9-based genome-wide screening to identify genetic determinants of PARP inhibitor response and resistance in BRCA-mutated breast cancer. These PARP inhibitors block the activity of the PARP protein, causing the single-strand DNA break to double-strand DNA break during replication due to replication fork collapse. Thus, the cancer cell DNA impairs DNA repair through defective homologous recombination. However, BRCA-mutated cells may endure resistance to PARP inhibitors due to BRCA reversion mutations, restoration of homologous recombination, 53BP1 pathway alterations, replication fork protection, drug efflux mechanisms, and the tumour microenvironment. CRISPR-Cas9 technology is an emerging genome-editing tool designed to identify the gene causing drug resistance and response. It systematically identifies determinants, synthetic lethal partners, and DNA damage response regulators using sgRNA libraries and next-generation sequencing. These findings support the development of combination therapy, PARP inhibitors with ATR or other DNA-damage response inhibitors, involved in biomarker discovery, personalised treatment, and improving precision medicine in breast cancer.