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. Author manuscript; available in PMC: 2024 May 29.
Published in final edited form as: Nat Rev Drug Discov. 2022 Oct 6;22(1):38–58. doi: 10.1038/s41573-022-00558-5

Fig. 5 |. Mechanisms of ATR–CHK1–WEE1 inhibitors to overcome PARP inhibitor resistance.

Fig. 5 |

The top panel shows mechanisms of poly[ADP-ribose]polymerase (PARP) inhibitor (PARPi) resistance. The main steps of the homologous recombination repair (HRR) pathway are shown at the left: DNA end resection on double-strand breaks (DSBs), RAD51 loading, homologous strand invasion and DNA synthesis. HRR deficiency makes cells sensitive to PARPi. Reversion mutations in BRCA1 and BRCA2, and RAD51 paralogues can restore HRR. CtIP and MRN are nucleases responsible for initial DNA end resection. MRN is a nuclease complex formed by MRE11-RAD50-NBS1. Loss of proteins that inhibit DNA end resection, such as 53BP1 and shieldin complex proteins, or upregulation of proteins that promote end resection, such as TRIP13 and USP15, can restore end resection in BRCA1-deficient cells, promoting PARPi resistance. The central panel shows how poly(ADP-ribose) glycohydrolase (PARG) counteracts PARP1-mediated PARylation (shown in yellow). Accordingly, loss of expression of PARG can lead to upregulation of PAR despite PARP1 inhibition, increasing replication stress and activating the ATR–CHK1–WEE1 pathway. The top right panel shows a stalled fork undergoing fork reversal. Fork protectors (shown by the grey, yellow and blue circles) such as BRCA1, BRCA2, RAD51 and PARP1 stabilize the fork, allowing DNA repair and fork restart. In the absence of fork protectors, nucleases (shown in red) such as MRE11 can degrade the reversed forks. Accordingly, loss of fork remodelling factors such as SMARCAL1, loss of recruiters of end resection such as PTIP, MLL3 and MLL4, and overexpression of fork protectors such as Fanconi anaemia group D2 protein (FANCD2), can lead to fork stabilization and PARPi resistance. The bottom panels show how ataxia telangiectasia mutated (ATM) and Rad3-related inhibitors (ATRi), CHK1 inhibitors (CHK1i) and WEE1 inhibitors (WEE1i) can overcome PARPi resistance. ATRi, CHK1i and WEE1i can cause HRR deficiency by decreasing BRCA2 and RAD51 recruitment (bottom left panel). They can suppress activation of the ATR pathway, which may be overactivated by PARG loss (bottom centre panel), and promote fork instability by reactivating SMARCAL1 and preventing RAD51 recruitment to the reversed fork (bottom right panel). SLFN11, Schlafen family member 11.