Fig. 6: Proposed mechanism of action underpinning observed potentiation of PARPi with addition of ATR/CHK1/WEE1 inhibition.

In HRD and in HRP cells PARPi causes replication stress that signals via ATR-CHK1-WEE1 to S phase and G2/M phase arrest and to HRR either via WEE1-mediated effects or via an intermediary (?). The outcome of the effects of PARPi alone are shown in white boxes and the outcome of the combination of the PARPi with an inhibitor of ATR, CHK1 or WEE1 is shown in purple boxes. In HRD cells: PARPi exposure results in RS, S-phase accumulation and cell death due to failure to resolve/repair PARPi-induced RS-DNA damage. The ATR, CHK1, WEE1 inhibitors, although preventing DNA damage activation of cell cycle arrest, do not increase the synthetic lethality of the HRD phenotype with PARPi and have no impact on the survival of these cells. In HRP cells: PARPi exposure results in RS and S-phase accumulation but cells survive by virtue of the ability to resolve/repair RS-DNA damage by HRR. The ATR, CHK1, WEE1 inhibitors, prevent DNA damage activation of cell cycle arrest, but primarily act by inhibiting HRR, thereby inducing an HRD phenotype and hence induced synthetic lethality with the PARPi and have a profound impact on the survival of these cells.