Inhibitors of DNA double-strand break repair at the crossroads of cancer therapy and genome editing

Conventional cancer treatment modalities such as radiation and chemotherapy, cause cancer cell death by inducing DNA damage, particularly DNA strand breaks. Over the years, newer avenues have emerged for overcoming radio/chemoresistance by harnessing repair proteins as targets for small molecule inhibitors. Analysis of genome-wide expression data in cancer subtypes and understanding synthetic lethal interactions among repair pathways are important stepping-stones. Several inhibitors targeting DNA strand break repair proteins have yielded good effects in preclinical studies, and have the potential to be developed as therapeutics in cancer as monotherapy or in combination with radiation and chemotherapy. Furthermore, these small molecule inhibitors can aid in precise genome editing (using CRISPR) by harnessing the differential levels of repair inside cells. Shifting the repair balance towards homology-directed repair using inhibitors of NHEJ or stimulators of HR has yielded promising effects alongside CRISPR in cells and several disease models. In short, DNA strand break repair inhibitors are the forerunners in cancer therapy and genome editing, working in concert with the established artillery in the field.