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

Zach, Róbert, Annis, Michael, Martin-Guerrero, Sandra M., Alatawi, Abdulrahman, Chia, Kim Hou, Meredith, Megan, Osborn, Kay, Peter, Nisha, Pearce, William, Booth, Jessica, Rajasekaran, Mohan, Dias, Samantha, Coleman-Evans, Lily, Foster, William R., Harper, Jon A., Herbert, Alex D., Tighe, Catherine, Reuillon, Tristan, West, Ryan, Busby, Oliver, Burdova, Kamila, Crepin, Damien, Ortoll, Sergi, Vaeteewoottacharn, Kulthida, Dejsuphong, Donniphat, Spencer, John, Patel, Hitesh, Le Grand, Darren, Hunt, Thomas A., Andrews, David M., Yamano, Hiroyuki, Cutillas, Pedro R., Oliver, Antony W., Ward, Simon E. ORCID: https://orcid.org/0000-0002-8745-8377 and Hochegger, Helfrid 2025. The balance between B55α and Greatwall expression levels predicts sensitivity to Greatwall inhibition in cancer cells. Nature Communications 16 (1) , 8016. 10.1038/s41467-025-62943-z

	PDF (Supplementary figures) - Supplemental Material Available under License Creative Commons Attribution. Download (62MB)
	PDF - Published Version Available under License Creative Commons Attribution. Download (13MB)

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
Date of First Compliant Deposit:	1 September 2025
Date of Acceptance:	30 July 2025
Last Modified:	01 Sep 2025 13:16
URI:	https://orca.cardiff.ac.uk/id/eprint/180787

Actions (repository staff only)

Edit Item