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

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.

Keywords: DNA damage response (DDR); Wee1; cancer therapy; cell cycle; kinase; synthetic lethality.

Figure 1

(A) The 642 amino acid long protein kinase Wee1 contains a N-terminal regulatory domain (dark blue), a kinase domain (yellow green), and a short C-terminal domain (gray). The diagram also shows a nuclear localization sequence (NLS; orange), a nuclear export sequence (NES; green), a highly conserved regulatory Wee1 box (red), and four cyclin binding motifs (RxL1, RxL2, RxL3, and RxL4; black). (B) Regulation of the cell cycle via phosphorylation of Cyclin-Dependent Kinases (CDKs) by Wee1 and the related protein kinase MYT1. (C) Images of HeLa cells in metaphase undergoing unperturbed mitosis or centromere fragmentation due to mitotic catastrophe as a result of premature entry into mitosis. (chromosomes, blue; tubulin, red; centromeres, green) (D) The fateful triangle underlying the conditional synthetic lethality observed in cancer cells leading to selective killing by combined ATR and Wee1 inhibition.