Targeting the Wnt signaling pathway in colorectal cancer

Abstract

Introduction: The treatment of patients with advanced colorectal cancer still remains challenging, and identification of new target molecules and therapeutic avenues remains a priority. The great majority of colorectal cancers have mutations in one of two genes involved in the Wnt signaling pathway: the adenomatous polyposis coli (APC) and β-catenin (CTNNB1) genes. Up to now, however, no therapeutics for targeting this pathway have been established.

Areas covered: This review article begins with a brief summary of Wnt signaling from the viewpoints of genetics, cancer stem cell biology, and drug development. We then overview current attempts to develop drugs directed at various components of the Wnt signaling pathway.

Expert opinion: APC is a tumor suppressor, and therefore only downstream signal transducers of the APC protein can be considered as targets for pharmaceutical intervention. TRAF2 and NCK-interacting protein kinase (TNIK) was identified as the most downstream regulator of Wnt signaling by two independent research groups, and several classes of small-molecule inhibitors targeting this protein kinase have been developed. TNIK is a multifunctional protein with actions that extend beyond Wnt signaling regulation. Such TNIK inhibitors are expected to have a large variety of clinical applications.

Keywords:

• cancer stem cell
• colorectal cancer
• T-cell factor-4
• TRAF2 and NCK-interacting protein kinase
• Wnt signaling

Acknowledgements

We are grateful to Ms. Naoko Goto for technical assistance.

Declaration of interest

M Sawa is an employee of Carna Biosciences, Inc. (Kobe, Japan). M Sawa and T Yamada were supported in this study by the Program for Promotion of Fundamental Studies in Health Sciences conducted by the National Institute of Biomedical Innovation of Japan. T Yamada received grant funding from the National Cancer Center (Japan) Research and Development Fund. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

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