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

Jordan C.J. Wilson; Jia Yi 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; Stephen P. Jackson

doi:10.1038/s41467-025-64050-5

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

Jordan C.J. Wilson
, Jia Yi 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

Stephen P. Jackson (Lead / Corresponding author)

Cancer Research

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

24 Downloads (Pure)

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.

Original language	English
Article number	8983
Journal	Nature Communications
Volume	16
Issue number	1
Early online date	9 Oct 2025
DOIs	https://doi.org/10.1038/s41467-025-64050-5
Publication status	Published - Dec 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General
General Physics and Astronomy

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Cite this

Wilson, J. C. J., Zhu, J. Y., Vinciauskaite, V., Lloyd, E. G., Lam, S., Hart, A., Goh, C. G., Bou-Dagher, F., Razumkov, H., Kobel, L., Kontarakis, Z., Fielden, J., Schlapansky, M. F., Loizou, J. I., Villunger, A., Corn, J. E., Biffi, G., Masson, G. R., Marciniak, S. J., ... Jackson, S. P. (2025). WEE1 inhibitors synergise with mRNA translation defects via activation of the kinase GCN2. Nature Communications, 16(1), Article 8983. https://doi.org/10.1038/s41467-025-64050-5

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title = "WEE1 inhibitors synergise with mRNA translation defects via activation of the kinase GCN2",

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.",

author = "Wilson, \{Jordan C.J.\} and Zhu, \{Jia Yi\} and Vanesa Vinciauskaite and Lloyd, \{Eloise G.\} and Simon Lam and Alexandra Hart and Goh, \{Chen Gang\} and Fadia Bou-Dagher and Hlib Razumkov and Lena Kobel and Zacharias Kontarakis and John Fielden and Schlapansky, \{Moritz F.\} and Loizou, \{Joanna I.\} and Andreas Villunger and Corn, \{Jacob E.\} and Giulia Biffi and Masson, \{Glenn R.\} and Marciniak, \{Stefan J.\} and Bader, \{Aldo S.\} and Jackson, \{Stephen P.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1038/s41467-025-64050-5",

language = "English",

volume = "16",

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Wilson, JCJ, Zhu, JY, Vinciauskaite, V, Lloyd, EG, Lam, S, Hart, A, Goh, CG, Bou-Dagher, F, Razumkov, H, Kobel, L, Kontarakis, Z, Fielden, J, Schlapansky, MF, Loizou, JI, Villunger, A, Corn, JE, Biffi, G, Masson, GR, Marciniak, SJ, Bader, AS & Jackson, SP 2025, 'WEE1 inhibitors synergise with mRNA translation defects via activation of the kinase GCN2', Nature Communications, vol. 16, no. 1, 8983. https://doi.org/10.1038/s41467-025-64050-5

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AU - Wilson, Jordan C.J.

AU - Zhu, Jia Yi

AU - Vinciauskaite, Vanesa

AU - Lloyd, Eloise G.

AU - Lam, Simon

AU - Hart, Alexandra

AU - Goh, Chen Gang

AU - Bou-Dagher, Fadia

AU - Razumkov, Hlib

AU - Kobel, Lena

AU - Kontarakis, Zacharias

AU - Fielden, John

AU - Schlapansky, Moritz F.

AU - Loizou, Joanna I.

AU - Villunger, Andreas

AU - Corn, Jacob E.

AU - Biffi, Giulia

AU - Masson, Glenn R.

AU - Marciniak, Stefan J.

AU - Bader, Aldo S.

AU - Jackson, Stephen P.

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105018248707

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DO - 10.1038/s41467-025-64050-5

M3 - Article

C2 - 41068143

AN - SCOPUS:105018248707

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 8983

ER -

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

Abstract

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Structural insights into eIF2alpha kinases using Hydrogen Deuterium Exchange Mass Spectrometry

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

Abstract

UN SDGs

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

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Purchase of Sample Handling Robot And Mass Spec For Structural Spectrometry Drug Screening

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Structural insights into eIF2alpha kinases using Hydrogen Deuterium Exchange Mass Spectrometry

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