Targeting CK1δ and CK1ε as a New Therapeutic Approach for Clear Cell Renal Cell Carcinoma

Introduction: Kidney cancer ranks as the ninth most common cancer in men and the fourteenth in women globally, with renal cell carcinoma (RCC) being the most prevalent type. Despite advances in therapeutic strategies targeting angiogenesis and immune checkpoints, the absence of reliable markers for patient selection and limited duration of disease control underline the need for innovative approaches. CK16 and CK1 epsilon are highly conserved serine/threonine kinases involved in cell cycle regulation, apoptosis, and circadian rhythm. While CK16 dysregulation is reportedly associated with breast and bladder cancer progression, their role in RCC remains elusive. This study aimed to investigate the feasibility of CK16/epsilon as new therapeutic targets for RCC patients. Methods: The relationship between CK16/epsilon and RCC progression was evaluated by the analysis of microarray dataset and TCGA database. The anticancer activity of CK16/epsilon inhibitor was examined by MTT/SRB assay, and apoptotic cell death was analyzed by fl ow cytometry and Western blotting. Results: Our data demonstrate that the gene expression of CSNK1D and CSNK1E is significantly higher in clear cell RCC (ccRCC) tissues compared to normal kidney samples, which is correlated with lower survival rates in ccRCC patients. SR3029, a selective inhibitor targeting CK16/epsilon, significantly suppresses the viability and proliferation of ccRCC cell lines regardless of the status of VHL deficiency. Importantly, the inhibitor promotes the population of subG1 cells and induces apoptosis, and ectopically expression of CK16 partially rescued SR3029-induced apoptosis in ccRCC cells. Conclusion: These fi ndings underscore the crucial role of CK16 and CK1 epsilon in ccRCC progression, suggesting CK16/epsilon inhibitors as new therapeutic options for ccRCC patients. (c) 2024 S. Karger AG, Basel