The balance between B55α and Greatwall expression levels predicts sensitivity to Greatwall inhibition in cancer cells
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.
Article Details
Authors (35)
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 Le Grand
Thomas A. Hunt
David M. Andrews
Hiroyuki Yamano
Pedro R. Cutillas
Antony W. Oliver
Simon E. Ward
Helfrid Hochegger