Targeting DNA Damage Repair Pathways Beyond PARP Inhibition

Exploiting DNA damage repair (DDR) vulnerabilities has become a major focus in cancer drug development following the clinical success of poly (ADP-ribose) polymerase (PARP) inhibitors. Beyond PARP, inhibitors of multiple other DDR proteins have progressed from preclinical development to early-phase clinical trials. DNA damage repair inhibitors have shown promise both as a selective therapeutic strategy in genomically selected cancers harbouring specific genetic vulnerabilities, and as a potential treatment approach to overcome innate and acquired PARP inhibitor resistance. This review summarises the most recent DDR inhibitor clinical evidence, focusing on DDR signalling targets; ATR (ataxia telangiectasia and Rad3-related protein serine/threonine kinase), ATM (ataxia telangiectasia mutated kinase), DNA-PK (DNA-dependent protein kinase), CHK1 (checkpoint kinase 1), WEE1 and recently emerging DNA repair targets; RAD51, PolƟ (DNA polymerase theta), WRN (Werner syndrome helicase), USP1 (ubiquitin specific peptidase 1) and PARG (poly(ADP-ribose) glycohydrolase). We highlight both clinical successes and failures of DDR inhibitors as monotherapy or in combination with chemotherapy, PARP and other DDR inhibitors. The challenges that must be addressed to see the true potential of these agents are discussed. Finally, we consider future directions and the necessity for integration of biomarkers and genomic profiling in DDR inhibitor clinical trials to optimally identify patients with tumours genetically vulnerable, and so crucially, take advantage of the selective therapeutic opportunity provided by DDR inhibition.