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Therapeutic targeting of casein kinase 1δ in breast cancer

Laura H Rosenberg1, Marie Lafitte2, Victor Quereda2

  • 1Department 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.

Science Translational Medicine
|December 18, 2015
PubMed

Insights

Targeting casein kinase 1δ (CK1δ) shows promise for breast cancer treatment. Inhibiting CK1δ triggers cancer cell death and tumor regression in models, particularly those with Wnt/β-catenin pathway involvement.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Targeted cancer therapeutics require identification of specific oncogenic drivers.
  • Casein kinase 1 delta (CSNK1D) gene amplification and overexpression are observed in human breast tumors.
  • Certain breast cancer subtypes exhibit vulnerability to casein kinase 1 delta (CK1δ).

Purpose of the Study:

  • To investigate the therapeutic potential of targeting CK1δ in human breast cancer.
  • To elucidate the role of CK1δ in Wnt/β-catenin signaling in breast tumors.

Main Methods:

  • Selective knockdown of CK1δ in breast tumor cells.
  • Treatment with a potent and selective CK1δ inhibitor.
  • In vivo studies using orthotopic models of triple-negative breast cancer and HER2(+) breast cancer.
  • Analysis of Wnt/β-catenin signaling pathway activation.

Main Results:

  • CK1δ knockdown or inhibition induced apoptosis in CK1δ-expressing breast tumor cells ex vivo.
  • Therapeutic targeting of CK1δ led to tumor regression in triple-negative breast cancer models and growth inhibition in HER2(+) models.
  • Overexpression of CK1δ correlated with Wnt/β-catenin signaling activation in human breast tumors.
  • CK1δ inhibition blocked nuclear β-catenin accumulation and T cell factor transcriptional activity.
  • Constitutively active β-catenin could overcome the effects of CK1δ inhibition or silencing.

Conclusions:

  • CK1δ is a validated therapeutic target in specific human breast cancer subtypes.
  • Targeting CK1δ offers a promising strategy for treating breast cancers with Wnt/β-catenin pathway involvement.

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