Combination DNA Damage Response (DDR) Inhibitors to Overcome Drug Resistance in Ovarian Cancer.

The DNA damage response (DDR) results in activation of a series of key target kinases that respond to different DNA damage insults. DDR inhibitors such as PARP inhibitors lead to the accumulation of DNA damage in tumor cells and ultimately apoptosis. However, responses to DDRi monotherapy in the clinic are not durable and resistance ultimately develops. DDRi-DDRi combinations such as PARPi-ATRi, PAPRi-WEE1i and PARPi-AsiDNA can overcome multiple resistance mechanisms to PARP inhibition. In addition, DDRi-DDRi combinations can provide viable treatment options for patients with platinum-resistant disease. In the present chapter we discuss rationale of DDRi-DDRi strategies that capitalize on genomic alterations found in ovarian cancer and other solid tumors and may provide in the near future new treatment options for these patients.