WEE1 inhibitors synergise with mRNA translation defects via activation of the kinase GCN2
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.
Authors
- Andreas Villunger (ORCID: https://orcid.org/0000-0001-8259-4153)
- John Fielden (ORCID: https://orcid.org/0000-0002-9068-1844)
- Aldo S. Bader (ORCID: https://orcid.org/0000-0001-5760-5113)
- Zacharias Kontarakis (ORCID: https://orcid.org/0000-0001-8825-8513)
- Joanna I. Loizou (ORCID: https://orcid.org/0000-0003-1853-0424)
- Alexandra M. Hart (ORCID: https://orcid.org/0000-0002-4383-2160)
- Moritz F. Schlapansky (ORCID: https://orcid.org/0000-0001-6072-7840)
- Lena Kobel (ORCID: https://orcid.org/0000-0001-7949-141X)
- Vanesa Vinciauskaite (ORCID: https://orcid.org/0000-0001-9226-1731)
- Stephen P. Jackson (ORCID: https://orcid.org/0000-0001-9317-7937)
- Jordan Wilson (ORCID: https://orcid.org/0000-0001-7765-8597)
- Glenn R. Masson (ORCID: https://orcid.org/0000-0002-1386-4719)
- Giulia Biffi (ORCID: https://orcid.org/0000-0003-4592-0970)
- Jacob E. Corn (ORCID: https://orcid.org/0000-0002-7798-5309)
- Stefan John Marciniak (ORCID: https://orcid.org/0000-0001-8472-7183)
- Eloise G. Lloyd (ORCID: https://orcid.org/0000-0002-5258-4111)
- Simon Lam (ORCID: https://orcid.org/0000-0002-4476-0971)
- Jiayi Zhu (ORCID: https://orcid.org/0009-0000-4094-1735)
- Hlib Razumkov
- Chen Gang Goh (ORCID: https://orcid.org/0009-0009-3491-7603)
- Fadia Bou-Dagher
Institutions
- Austrian Academy of Sciences (AT)
- Institute of Cancer Research (GB)
- Innsbruck Medical University (AT)
- University of Dundee (GB)
- Universität Innsbruck (AT)
- University of Cambridge (GB)
- Breast Cancer Now (GB)
- Cancer Research UK (GB)
- Ninewells Hospital (GB)
- ETH Zurich (CH)
- Cancer Research UK Cambridge Center (GB)
- Comprehensive Cancer Center Vienna (AT)
- CeMM Research Center for Molecular Medicine (AT)
- Stanford Medicine (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-09
- DOI
- https://doi.org/10.1038/s41467-025-64050-5
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- AstraZeneca
- Cancer Research UK
- European Commission
- Boehringer Ingelheim Fonds
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Eidgenössische Technische Hochschule Zürich
- Cambridge Trust
- NOMIS Stiftung
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- Cancer Research UK Cambridge Institute, University of Cambridge