Evolving DNA repair synthetic lethality targets in cancer

DNA damage signaling response and repair (DDR) is a critical defense mechanism against genomic instability. Impaired DNA repair capacity is an important risk factor for cancer development. On the other hand, up-regulation of DDR mechanisms is a feature of cancer chemotherapy and radiotherapy resistance. Advances in our understanding of DDR and its complex role in cancer has led to several translational DNA repair-targeted investigations culminating in clinically viable precision oncology strategy using poly(ADP-ribose) polymerase (PARP) inhibitors in breast, ovarian, pancreatic, and prostate cancers. While PARP directed synthetic lethality has improved outcomes for many patients, the lack of sustained clinical response and the development of resistance pose significant clinical challenges. Therefore, the search for additional DDR-directed drug targets and novel synthetic lethality approaches is highly desirable and is an area of intense preclinical and clinical investigation. Here, we provide an overview of the mammalian DNA repair pathways and then focus on current state of PARP inhibitors (PARPi) and other emerging DNA repair inhibitors for synthetic lethality in cancer.