FIGURE 2.

Partial mechanisms of PARP inhibitor resistance in cancer. (A) Restoration of replication fork stability leads to PARP inhibitor resistance. When EZH2 or MLL3/4-PTIP is deficient, MUS81 and MRE11 recruitment fails, the replication fork is less attacked, and the replication fork is stable. (B) Decreased PARP1 trapping contributes to the development of PARP inhibitor resistance. PARP inhibitors reduce the catalytic activity of PARP1, so that PARP remains bound to DNA and cannot undergo subsequent repair. PARP1 mutations reduce PARP capture. (C) Increased drug efflux mediated by ABCB1 overexpression leads to a decrease in effective concentration in cancer cells and increased resistance to PARPi.