Preventing Damage Limitation: Targeting DNA-PKcs and DNA Double-Strand Break Repair Pathways for Ovarian Cancer Therapy

open access

...The promise of PARP inhibition strategies and DNA-PKcs as a therapeutic target highlights the importance of understanding the clinical significance of the functioning and defective DNA repair mechanisms in cancer. There remains the need to identify reliable biomarkers of tumor cell response and resistance to therapies targeting DNA repair proteins and indeed to identify and validate new therapeutic targets from this critical but insufficiently mined resource. The identification of patient subgroups who will benefit most from such strategies is also required – DDR proteins such as DNA-PKcs have been suggested to have a tumor-suppressive role in the early stages of carcinogenesis where ineffective DDR may contribute to the generation of genomic instability that drives tumor progression (99). As such, the development of DNA-PKcs inhibitions, and indeed other DDR targeted therapies, should be mindful of DNA damage thresholds that can be either oncogenic or tumor-suppressive, depending on the tumor stage. Together, such knowledge and understanding will translate into the development of new directed strategies that will help overcome clinical platinum resistance in ovarian cancer, and by that reduce patient mortality.