Therapeutic targeting of casein kinase 1δ in breast cancer

Laura H Rosenberg; Marie Lafitte; Victor Quereda; Wayne Grant; Weimin Chen; Mathieu Bibian; Yoshihiko Noguchi; Mohammad Fallahi; Chunying Yang; Jenny C Chang; William R Roush; John L Cleveland; Derek R Duckett

doi:10.1126/scitranslmed.aac8773

Therapeutic targeting of casein kinase 1δ in breast cancer

Sci Transl Med. 2015 Dec 16;7(318):318ra202. doi: 10.1126/scitranslmed.aac8773.

Authors

Affiliations

¹ 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.
² Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
³ Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA.
⁴ Informatics Core, The Scripps Research Institute, Jupiter, FL 33458, USA.
⁵ 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.
⁶ Methodist Cancer Center, Houston Methodist Hospital, 6445 Main Street, P21-34, Houston, TX 77030, USA.
⁷ Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Breast Neoplasms / drug therapy*
Breast Neoplasms / enzymology
Breast Neoplasms / genetics
Breast Neoplasms / pathology
Casein Kinase Idelta / antagonists & inhibitors*
Casein Kinase Idelta / genetics
Casein Kinase Idelta / metabolism
Cell Proliferation / drug effects
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 / pharmacology*
Purines / pharmacology*
RNA Interference
TCF Transcription Factors / metabolism
Time Factors
Transfection
Triple Negative Breast Neoplasms / drug therapy*
Triple Negative Breast Neoplasms / enzymology
Triple Negative Breast Neoplasms / genetics
Triple Negative Breast Neoplasms / pathology
Tumor Burden / drug effects
Wnt Signaling Pathway / drug effects
Xenograft Model Antitumor Assays
beta Catenin / metabolism

Substances

Antineoplastic Agents
CTNNB1 protein, human
Protein Kinase Inhibitors
Purines
SR-3029
TCF Transcription Factors
beta Catenin
Casein Kinase Idelta

Abstract

Publication types

MeSH terms

Substances

Grants and funding