Fig. 4.

Resistance mechanism to PARP inhibitors. Increased drug efflux. Overexpression of drug-efflux transporter genes, such as ABCB1, increases the number of drug effluxion pumps and prevents PARP inhibitors (PARPi) from reaching cell nucleus. Decreased PARP trapping. Deletion of PARP1 or mutations in its DNA-binding domains avoid trapping to occur. This confers cells with a resistance to PARPi. Alternatively, increased PARylation through loss of inhibitors, as PARG, produces the same effects with resistance to PARPi. Stabilization of stalled fork. Nucleases actions on nascent DNA are delayed or reduced by the inhibition of proteins in charge of their recruitment to the fork. Restoration of Homologous Recombination Repair (HRR). Mutational reversion or occurrence of a second mutation, which restores functional BRCA1/2 proteins, prevents the occurrence of synthetic lethality. Loss of inhibitors of HRR such as 53BP1 leads to the same resistance