WEE1 inhibitors synergise with mRNA translation defects via activation of the kinase GCN2

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• WEE1 kinase inhibitors show promise in cancer therapy.
• Understanding off-target effects is crucial for optimizing WEE1 inhibitor efficacy.

Purpose of the Study:

• To investigate synergistic interactions between WEE1 inhibitors and mRNA translation defects.
• To elucidate the role of the integrated stress response (ISR) in WEE1 inhibitor toxicity.
• To identify strategies for mitigating off-target effects of WEE1 inhibitors.

Main Methods:

• Pooled CRISPRi screening to identify genetic modifiers of WEE1 inhibitor sensitivity.
• Assays to measure ISR activation and genotoxic stress.
• Evaluation of PROTAC-based WEE1 inhibitors and molecular glues for ISR activation.

Main Results:

• Depletion of GSPT1 and ALKBH8 conferred hypersensitivity to the WEE1 inhibitor AZD1775.
• ISR activation, mediated by GCN2, was induced by off-target activity of WEE1 inhibitors.
• PROTAC-based inhibitors and molecular glues exhibited reduced ISR activation.
• WEE1 inhibitors can cause dual toxicity via ISR activation and genotoxic stress, independent of WEE1 or cell cycle.

Conclusions:

• WEE1 inhibitors can activate the ISR, contributing to synergistic effects with mRNA translation defects.
• Targeting ISR activation or combining WEE1 inhibitors with mRNA translation modulators may enhance cancer therapy.
• Developing WEE1 inhibitors with reduced off-target ISR activation is essential for improving therapeutic outcomes.