Targeting the DNA Damage Response for Cancer Therapy by Inhibiting the Kinase Wee1.

Amirali B Bukhari,Armin M Gamper,Gordon K Chan

doi:10.3389/fonc.2022.828684

Abstract

Cancer cells typically heavily rely on the G2/M checkpoint to survive endogenous and exogenous DNA damage, such as genotoxic stress due to genome instability or radiation and chemotherapy. The key regulator of the G2/M checkpoint, the cyclin-dependent kinase 1 (CDK1), is tightly controlled, including by its phosphorylation state. This posttranslational modification, which is determined by the opposing activities of the phosphatase cdc25 and the kinase Wee1, allows for a more rapid response to cellular stress than via the synthesis or degradation of modulatory interacting proteins, such as p21 or cyclin B. Reducing Wee1 activity results in ectopic activation of CDK1 activity and drives premature entry into mitosis with unrepaired or under-replicated DNA and causing mitotic catastrophe. Here, we review efforts to use small molecule inhibitors of Wee1 for therapeutic purposes, including strategies to combine Wee1 inhibition with genotoxic agents, such as radiation therapy or drugs inducing replication stress, or inhibitors of pathways that show synthetic lethality with Wee1. Furthermore, it become increasingly clear that Wee1 inhibition can also modulate therapeutic immune responses. We will discuss the mechanisms underlying combination treatments identifying both cell intrinsic and systemic anti-tumor activities.

Highlights

Cancer cells typically heavily rely on the G2/M checkpoint to survive endogenous and exogenous DNA damage, such as genotoxic stress due to genome instability or radiation and chemotherapy
The pathways initiated by the apical kinases Ataxia Telangiectasiamutated (ATM) [3, 4] and Ataxia telangiectasia and Rad3 related (ATR) [5] relay the damage signal to downstream effectors, including the tumor suppressor p53, a central node in the DNA damage response [6]
As all checkpoints are governed by cyclin-dependent kinases (CDKs), all DNA damage pathways converge on the regulation of the CDK activity

Summary

Introduction

Cancer cells typically heavily rely on the G2/M checkpoint to survive endogenous and exogenous DNA damage, such as genotoxic stress due to genome instability or radiation and chemotherapy. (2022) Targeting the DNA Damage Response for Cancer Therapy by Inhibiting the Kinase Wee1. The key role of Wee1 in regulating the G2/M checkpoint in response to DNA damage has made it an attractive target for cancer therapy.

Results

Conclusion