title: Targeting homologous recombination, new pre-clinical and clinical therapeutic combinations inhibiting RAD51.
abstract: The DNA damage response (DDR) is essential for maintaining genomic stability and cell survival. However, when tumour cells with deficiencies in HR are faced with radio- and chemotherapies they are forced to rely on error-prone, alternative repair pathways or aberrant HR for survival; threatening genome integrity and driving further mutation. Accurate therapeutic targeting of the key drivers of DNA repair can circumvent survival pathways and avoid aggressive therapy resistant mutants. Several studies have identified that stabilization of the cancer genome in HR deficient cells can be achieved by overexpression of the recombinase RAD51. Radio- and chemotherapeutic resistance is associated with overactive HR repair mechanisms. However no clinical trials have directly targeted RAD51, despite RAD51 displaying synergy in several drug screens against multiple cancer types. Currently synthetic lethality targeting the DDR pathways and HR deficiency has had clinical success with BRCA1 functional loss and PARP inhibition. In this review we suggest that clinical outcomes could be improved by additionally targeting RAD51. We examine the latest developments in directly and indirectly targeting RAD51. We scrutinize the potential treatment efficacy and future clinical applications of RAD51 inhibitors as single agents and in combination with other therapies and consider the best therapeutic options.
authors.affiliation: Signal Transduction Laboratory, QIMR Berghofer, Herston Rd, Herston, QLD 4006, Australia. Electronic address: ambber.ward@qimrberghofer.edu.au.
authors.forename: Ambber
authors.initials: A
authors.lastname: Ward
authors.affiliation: Signal Transduction Laboratory, QIMR Berghofer, Herston Rd, Herston, QLD 4006, Australia. Electronic address: kumkum.khanna@qimrberghofer.edu.au.
authors.forename: Kum Kum
authors.initials: KK
authors.lastname: Khanna
authors.affiliation: Signal Transduction Laboratory, QIMR Berghofer, Herston Rd, Herston, QLD 4006, Australia. Electronic address: adrian.wiegmans@qimrberghofer.edu.au.
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Wiegmans
mesh_terms: D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D059765:Homologous Recombination; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051135:Rad51 Recombinase / Q000037:antagonists & inhibitors*
chemical_list: D051135:Rad51 Recombinase
keywords: Combination therapy; DNA damage response; Homologous recombination; RAD51; Synthetic lethality; Targeted therapy