PARP Inhibitor Resistance Mechanisms and Implications for Post-Progression Combination Therapies

Abstract

The use of PARP inhibitors (PARPi) is growing widely as FDA approvals have shifted its use from the recurrence setting to the frontline setting. In parallel, the population developing PARPi resistance is increasing. Here we review the role of PARP, DNA damage repair, and synthetic lethality. We discuss mechanisms of resistance to PARP inhibition and how this informs on novel combinations to re-sensitize cancer cells to PARPi.

Keywords: BRCA; DNA damage repair; PARP inhibitor; PARP inhibitor resistance; homologous recombination; ovarian cancer; replication fork.

Figure 1

Thematic mechanisms of resistance to PARP inhibition.

Figure 2

Rationale for re-sensitization to PARPi. Almost all HGSOC harbor mutant p53, with cell cycle dysregulation at baseline. Inhibition of ATM or ATR further prevents the appropriate halting of the cell cycle. Using agents that reestablish HR deficiency allows for the accumulation of endogenous and exogenous DNA damage, trapped PARP, and replication stress, ultimately leading to mitotic catastrophe and cell death.