Dual inhibition of PLK1 and CDK1/2 selectively suppresses the growth of canine squamous cell carcinoma cell lines with truncating TP53 mutations

Abstract

Canine squamous cell carcinoma (SCC) remains a clinically challenging malignancy with limited therapeutic options for advanced or non-resectable cases. In this study, canine SCC cell lines harboring truncating TP53 mutations were identified, and TP53-associated therapeutic vulnerabilities were investigated. Genetic analysis of TP53 in five canine SCC cell lines revealed premature termination codon–generating mutations in two lines: c.207_208insC (p.Thr70Hisfs*82) and c.234_235delinsA (p.Trp78*). TP53 protein could not be detected in western blot analysis of cell lines carrying these mutations. Although treatment with polo-like kinase 1 (PLK1) inhibitors alone (volasertib, BI2536, or GSK461364) did not induce selective growth inhibition, combined treatment with volasertib and the cyclin-dependent kinase (CDK)1/2 inhibitor BMS-265246 resulted in selective and synergistic growth suppression in TP53 -mutant cell lines. PLK1 and CDK1/2 cooperatively regulate G2/M progression via interconnected signaling pathways negatively regulated by TP53. Loss of TP53 may therefore increase cellular dependence on PLK1-CDK1/2 signaling, providing a potential mechanistic basis for the observed selective sensitivity to dual inhibition. These findings highlight the potential for exploiting TP53 loss–associated vulnerabilities in canine SCC and suggest further investigation into PLK1-CDK1/2 co-targeting strategies is warranted.