The balance between B55α and Greatwall expression levels predicts sensitivity to Greatwall inhibition in cancer cells
2
Issued Date
2025-12-01
Resource Type
eISSN
20411723
Scopus ID
2-s2.0-105014215654
Journal Title
Nature Communications
Volume
16
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Nature Communications Vol.16 No.1 (2025)
Suggested Citation
Zach R., Annis M., Martin-Guerrero S.M., Alatawi A., Chia K.H., Meredith M., Osborn K., Peter N., Pearce W., Booth J., Rajasekaran M., Dias S., Coleman-Evans L., Foster W.R., Harper J.A., Herbert A.D., Tighe C., Reuillon T., West R., Busby O., Burdova K., Crepin D., Ortoll S., Vaeteewoottacharn K., Dejsuphong D., Spencer J., Patel H., Le Grand D., Hunt T.A., Andrews D.M., Yamano H., Cutillas P.R., Oliver A.W., Ward S.E., Hochegger H. The balance between B55α and Greatwall expression levels predicts sensitivity to Greatwall inhibition in cancer cells. Nature Communications Vol.16 No.1 (2025). doi:10.1038/s41467-025-62943-z Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/111909
Title
The balance between B55α and Greatwall expression levels predicts sensitivity to Greatwall inhibition in cancer cells
Author(s)
Zach R.
Annis M.
Martin-Guerrero S.M.
Alatawi A.
Chia K.H.
Meredith M.
Osborn K.
Peter N.
Pearce W.
Booth J.
Rajasekaran M.
Dias S.
Coleman-Evans L.
Foster W.R.
Harper J.A.
Herbert A.D.
Tighe C.
Reuillon T.
West R.
Busby O.
Burdova K.
Crepin D.
Ortoll S.
Vaeteewoottacharn K.
Dejsuphong D.
Spencer J.
Patel H.
Le Grand D.
Hunt T.A.
Andrews D.M.
Yamano H.
Cutillas P.R.
Oliver A.W.
Ward S.E.
Hochegger H.
Annis M.
Martin-Guerrero S.M.
Alatawi A.
Chia K.H.
Meredith M.
Osborn K.
Peter N.
Pearce W.
Booth J.
Rajasekaran M.
Dias S.
Coleman-Evans L.
Foster W.R.
Harper J.A.
Herbert A.D.
Tighe C.
Reuillon T.
West R.
Busby O.
Burdova K.
Crepin D.
Ortoll S.
Vaeteewoottacharn K.
Dejsuphong D.
Spencer J.
Patel H.
Le Grand D.
Hunt T.A.
Andrews D.M.
Yamano H.
Cutillas P.R.
Oliver A.W.
Ward S.E.
Hochegger H.
Corresponding Author(s)
Other Contributor(s)
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.