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

  • Nat Commun. 2025 Oct 9;16(1):8983. doi: 10.1038/s41467-025-64050-5.
Jordan C J Wilson  1  2  3 ,  JiaYi Zhu  4 ,  Vanesa Vinciauskaite  5 ,  Eloise G Lloyd  1 ,  Simon Lam  1 ,  Alexandra Hart  1 ,  Chen Gang Goh  1 ,  Fadia Bou-Dagher  1 ,  Hlib Razumkov  6  7 ,  Lena Kobel  8 ,  Zacharias Kontarakis  9 ,  John Fielden  8 ,  Moritz F Schlapansky  8 ,  Joanna I Loizou  2  3  10 ,  Andreas Villunger  3  11 ,  Jacob E Corn  8 ,  Giulia Biffi  1 ,  Glenn R Masson  5 ,  Stefan J Marciniak  4 ,  Aldo S Bader  1 ,  Stephen P Jackson  12
Affiliations
  • 1. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • 2. Center for Cancer Research, Comprehensive Cancer Centre, Medical University of Vienna, Vienna, Austria.
  • 3. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 4. Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, UK.
  • 5. Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, UK.
  • 6. Department of Chemistry, Stanford School of Humanities and Sciences, Stanford University, Stanford, CA, USA.
  • 7. Department of Chemical and Systems Biology, ChEM-H, Stanford School of Medicine, Stanford University, Stanford, CA, USA.
  • 8. Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
  • 9. Genome Engineering and Measurement Lab, ETH Zurich, Zurich, Switzerland.
  • 10. Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
  • 11. Institute of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
  • 12. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK. [email protected].
PMID: 41068143 DOI: 10.1038/s41467-025-64050-5
Abstract

Inhibitors of the protein kinase Wee1 have emerged as promising agents for Cancer therapy. In this study, we uncover synergistic interactions between Wee1 small-molecule inhibitors and defects in mRNA translation, mediated by activation of the integrated stress response (ISR) through the kinase GCN2. Using a pooled CRISPRi screen, we identify GSPT1 and ALKBH8 as factors whose depletion confer hypersensitivity to the Wee1 Inhibitor, AZD1775. We demonstrate that this synergy depends on ISR activation, which is induced by the off-target activity of Wee1 inhibitors. Furthermore, PROTAC-based Wee1 inhibitors and Molecular Glues show reduced or no ISR activation, suggesting potential strategies to minimise off-target toxicity. Our findings reveal that certain Wee1 inhibitors elicit dual toxicity via ISR activation and genotoxic stress, with ISR activation being independent of Wee1 itself or cell-cycle status. This dual mechanism highlights opportunities for combination therapies, such as pairing Wee1 inhibitors with agents targeting the mRNA translation machinery. This study also underscores the need for more precise Wee1 targeting strategies to mitigate off-target effects, with implications for optimising the therapeutic potential of Wee1 inhibitors.

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