Therapeutic targeting of casein kinase 1δ in breast cancer

Identification of specific drivers of human cancer is required to instruct the development of targeted therapeutics. We demonstrate that CSNK1D is amplified and/or overexpressed in human breast tumors and that casein kinase 1 delta (CK1 delta) is a vulnerability of human breast cancer subtypes overexpressing this kinase. Specifically, selective knockdown of CK1 delta, or treatment with a highly selective and potent CK1 delta inhibitor, triggers apoptosis of CK1 delta-expressing breast tumor cells ex vivo, tumor regression in orthotopic models of triple-negative breast cancer, including patient-derived xenografts, and tumor growth inhibition in human epidermal growth factor receptor 2-positive (HER2(+)) breast cancer models. We also show that Wnt/beta-catenin signaling is a hallmark of human tumors overexpressing CK1 delta, that disabling CK1 delta blocks nuclear accumulation of beta-catenin and T cell factor transcriptional activity, and that constitutively active beta-catenin overrides the effects of inhibition or silencing of CK1 delta. Thus, CK1 delta inhibition represents a promising strategy for targeted treatment in human breast cancer with Wnt/beta-catenin involvement.