sr-3029 and Breast-Neoplasms

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 1δ (CK1δ) is a vulnerability of human breast cancer subtypes overexpressing this kinase. Specifically, selective knockdown of CK1δ, or treatment with a highly selective and potent CK1δ inhibitor, triggers apoptosis of CK1δ-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/β-catenin signaling is a hallmark of human tumors overexpressing CK1δ, that disabling CK1δ blocks nuclear accumulation of β-catenin and T cell factor transcriptional activity, and that constitutively active β-catenin overrides the effects of inhibition or silencing of CK1δ. Thus, CK1δ inhibition represents a promising strategy for targeted treatment in human breast cancer with Wnt/β-catenin involvement.

Topics: Animals; Antineoplastic Agents; Apoptosis; beta Catenin; Breast Neoplasms; Casein Kinase Idelta; Cell Proliferation; Computational Biology; Databases, Genetic; Dose-Response Relationship, Drug; Drug Design; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Mice, Nude; Mice, SCID; Molecular Targeted Therapy; Protein Kinase Inhibitors; Purines; RNA Interference; TCF Transcription Factors; Time Factors; Transfection; Triple Negative Breast Neoplasms; Tumor Burden; Wnt Signaling Pathway; Xenograft Model Antitumor Assays