The balance between B55α and Greatwall expression levels predicts sensitivity to Greatwall inhibition in cancer cells

Róbert Zach (), Michael Annis, Sandra M. Martin-Guerrero, Abdulrahman Alatawi, Kim Hou Chia, Megan Meredith, Kay Osborn, Nisha Peter, William Pearce, Jessica Booth, Mohan Rajasekaran, Samantha Dias, Lily Coleman-Evans, William R. Foster, Jon A. Harper, Alex D. Herbert, Catherine Tighe, Tristan Reuillon, Ryan West, Oliver Busby, Kamila Burdova, Damien Crepin, Sergi Ortoll, Kulthida Vaeteewoottacharn, Donniphat Dejsuphong, John Spencer, Hitesh Patel, Darren Grand, Thomas A. Hunt, David M. Andrews, Hiroyuki Yamano, Pedro R. Cutillas, Antony W. Oliver, Simon E. Ward and Helfrid Hochegger ()
Additional contact information
Róbert Zach: University of Sussex
Michael Annis: University of Sussex
Sandra M. Martin-Guerrero: Queen Mary University of London
Abdulrahman Alatawi: University of Sussex
Kim Hou Chia: University College London Cancer Institute
Megan Meredith: University of Sussex
Kay Osborn: University of Sussex
Nisha Peter: University of Sussex
William Pearce: University of Sussex
Jessica Booth: University of Sussex
Mohan Rajasekaran: University of Sussex
Samantha Dias: University of Sussex
Lily Coleman-Evans: University of Sussex
William R. Foster: University of Sussex
Jon A. Harper: University of Sussex
Alex D. Herbert: University of Sussex
Catherine Tighe: University of Sussex
Tristan Reuillon: University of Sussex
Ryan West: University of Sussex
Oliver Busby: University of Sussex
Kamila Burdova: University of Sussex
Damien Crepin: University of Sussex
Sergi Ortoll: University of Sussex
Kulthida Vaeteewoottacharn: Khon Kaen University
Donniphat Dejsuphong: Mahidol University
John Spencer: University of Sussex
Hitesh Patel: Cardiff University
Darren Grand: Cardiff University
Thomas A. Hunt: AstraZeneca
David M. Andrews: AstraZeneca
Hiroyuki Yamano: University College London Cancer Institute
Pedro R. Cutillas: Queen Mary University of London
Antony W. Oliver: University of Sussex
Simon E. Ward: Cardiff University
Helfrid Hochegger: University of Sussex

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract The Greatwall kinase inhibits PP2A-B55 phosphatase activity during mitosis to stabilise critical Cdk1-driven mitotic phosphorylation. Although Greatwall represents a potential oncogene and prospective therapeutic target, our understanding of the cellular and molecular consequences of chemical Greatwall inactivation remains limited. To address this, we introduce C-604, a highly selective Greatwall inhibitor, and characterise both immediate and long-term cellular responses to the chemical attenuation of Greatwall activity. We demonstrate that Greatwall inhibition causes systemic destabilisation of the mitotic phosphoproteome, premature mitotic exit and pleiotropic cellular pathologies. Importantly, we show that the cellular and molecular abnormalities associated with reduced Greatwall activity are specifically dependent on the B55α isoform, rather than other B55 variants, underscoring PP2A-B55α phosphatases as key mediators of the cytotoxic effects of Greatwall-targeting agents in human cells. Additionally, we establish that sensitivity to Greatwall inhibition varies in different cell line models and that dependency on Greatwall activity reflects the balance between Greatwall and B55α expression levels. Our findings highlight Greatwall dependency as a cell-specific vulnerability and propose the B55α-to-Greatwall expression ratio as a predictive biomarker of cellular responses to Greatwall-targeted therapeutics.

Date: 2025
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DOI: 10.1038/s41467-025-62943-z

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