Fig. 1.

PARP inhibitors: Some possible mechanisms of action and resistance. The left panel illustrates two possible mechanisms of action of PARPi. Upper pathway: Inhibition of PARP enzyme activity or catalytic inhibition interferes with the repair of single-strand breaks, leading to stalled DNA replication forks that requires HR repair. In HR-deficient tumours, such as those with BRCAm, PARP inhibition results in synthetic lethality. Lower pathway: PARP trapping refers to trapping of PARP proteins on DNA, which also leads to replication fork damage, but because this pathway utilises additional repair mechanisms, it is not restricted to tumours with HR deficiency. The right panel illustrates three possible mechanisms of resistance to PARPi. These include: (1) secondary mutations in BRCA genes that restore BRCA function and HR; (2) somatic mutation of TP53BP1, causing partial restoration of HR; and (3) increased PARPi efflux mediated by MDR1/P-glycoprotein 1, preventing the drugs from acting at the appropriate sites. The first two mechanisms of resistance restore HR and apply to PARP catalytic inhibition in HR-deficient tumours; whereas, the third mechanism applies to both mechanisms of action of PARPi. BRCAm BRCA mutation; HR homologous recombination; MDR1 multidrug resistance protein 1; p53BP1 tumour suppressor p53-binding protein 1; PARP poly(ADP-ribose) polymerase; PARPi PARP inhibitor