Casein Kinase 1δ Is a Potential Therapeutic Target in Breast Cancer

The serine/threonine kinase casein kinase 1δ (CK1δ, encoded by CSNK1D) has been suggested to contribute to mammary carcinogenesis in mice, but the role of CK1δ in human cancer has not been clearly defined. Rosenberg and colleagues found that CSNK1D was frequently overexpressed or amplified in human breast tumors, in particular those of the luminal B, HER2⁺, and basal-like subtypes. Silencing of CK1δ or treatment with a potent and selective small-molecule inhibitor of CK1δ and the highly related kinase CK1ϵ, SR-3029, induced apoptosis and suppressed the growth of CK1δ-overexpressing breast cancer cells; this effect was due to on-target inhibition of CK1δ. Furthermore, SR-3029 impaired xenograft tumor growth and prolonged survival in vivo, inducing regression of triple-negative tumors and significantly inhibiting tumor growth in a patient-derived xenograft model of basal-like invasive ductal carcinoma without overt toxicity. Gene expression analysis identified a correlation between expression of CK1δ and genes encoding components of the canonical WNT pathway, suggesting that CK1δ activates WNT signaling in human breast cancer. Consistent with this idea, CK1δ silencing or SR-3029 treatment was sufficient to reduce levels of nuclear β-catenin and β-catenin transcriptional activity in CK1δ-overexpressing cell lines and tumors. Depletion of β-catenin also selectively impaired the growth of CK1δ-overexpressing cells, whereas ectopic expression of constitutively active β-catenin mutants conferred resistance to CK1δ inhibition, supporting the importance of CK1δ–β-catenin signaling in breast cancer. Furthermore, overexpression of CK1δ enhanced the growth of breast cancer cells with low endogenous CK1δ levels in a β-catenin–dependent manner. These results provide insight into the role of CK1δ in human breast cancer and identify this kinase as a potential therapeutic target in a subset of human breast cancers with activation of WNT/β-catenin signaling.

Rosenberg LH, Lafitte M, Quereda V, Grant W, Chen W, Bibian M, et al. Therapeutic targeting of casein kinase 1δ in breast cancer. Sci Transl Med 2015;7:318ra202.