Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 7, Issue 318, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aac8773
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Funding
- NIH [CA175094]
- NIH Molecular Library Screening Center Network [U54MH074404]
- National Cancer Institute Comprehensive Cancer Center [P30-CA076292]
- Rendina Family Foundation
- Shear Family Foundation
- Think Pink Kids Foundation
- State of Florida to Scripps Florida
- Moffitt Cancer Center and Research Institute
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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.
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