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

Jordan C. J. Wilson, JiaYi Zhu, Vanesa Vinciauskaite, Eloise G. Lloyd, Simon Lam, Alexandra Hart, Chen Gang Goh, Fadia Bou-Dagher, Hlib Razumkov, Lena Kobel, Zacharias Kontarakis, John Fielden, Moritz F. Schlapansky, Joanna I. Loizou, Andreas Villunger, Jacob E. Corn, Giulia Biffi, Glenn R. Masson, Stefan J. Marciniak, Aldo S. Bader and Stephen P. Jackson ()
Additional contact information
Jordan C. J. Wilson: University of Cambridge
JiaYi Zhu: University of Cambridge
Vanesa Vinciauskaite: University of Dundee, Ninewells Hospital
Eloise G. Lloyd: University of Cambridge
Simon Lam: University of Cambridge
Alexandra Hart: University of Cambridge
Chen Gang Goh: University of Cambridge
Fadia Bou-Dagher: University of Cambridge
Hlib Razumkov: Stanford University
Lena Kobel: ETH Zurich
Zacharias Kontarakis: ETH Zurich
John Fielden: ETH Zurich
Moritz F. Schlapansky: ETH Zurich
Joanna I. Loizou: Medical University of Vienna
Andreas Villunger: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Jacob E. Corn: ETH Zurich
Giulia Biffi: University of Cambridge
Glenn R. Masson: University of Dundee, Ninewells Hospital
Stefan J. Marciniak: University of Cambridge
Aldo S. Bader: University of Cambridge
Stephen P. Jackson: University of Cambridge

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-64050-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64050-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-64050-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().