2. Academic Validation
  3. Therapeutic targeting of casein kinase 1δ in breast cancer

Therapeutic targeting of casein kinase 1δ in breast cancer

  • Sci Transl Med. 2015 Dec 16;7(318):318ra202. doi: 10.1126/scitranslmed.aac8773.
Laura H Rosenberg 1,  Marie Lafitte 2,  Victor Quereda 2,  Wayne Grant 2,  Weimin Chen 2,  Mathieu Bibian 3,  Yoshihiko Noguchi 3,  Mohammad Fallahi 4,  Chunying Yang 5,  Jenny C Chang 6,  William R Roush 3,  John L Cleveland 5,  Derek R Duckett 7
Affiliations

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].
PMID: 26676609 DOI: 10.1126/scitranslmed.aac8773
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.

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