title: Therapeutic targeting of casein kinase 1δ in breast cancer.
abstract: 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.
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA. Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, CB22 3AT, UK.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Rosenberg
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Lafitte
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Quereda
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Wayne
authors.initials: W
authors.lastname: Grant
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bibian
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Noguchi
authors.affiliation: Informatics Core, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Fallahi
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA. Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Chunying
authors.initials: C
authors.lastname: Yang
authors.affiliation: Methodist Cancer Center, Houston Methodist Hospital, 6445 Main Street, P21-34, Houston, TX 77030, USA.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Chang
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Roush
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA. Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Cleveland
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA. ducketdr@scripps.edu.
authors.forename: Derek R
authors.initials: DR
authors.lastname: Duckett
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D048148:Casein Kinase Idelta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology; D030541:Databases, Genetic; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008819:Mice, Nude; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D034622:RNA Interference; D051820:TCF Transcription Factors / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; D047428:Protein Kinase Inhibitors; D011687:Purines; C585785:SR-3029; D051820:TCF Transcription Factors; D051176:beta Catenin; D048148:Casein Kinase Idelta