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
  • 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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