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Targeting JAK kinase in solid tumors: emerging opportunities and challenges

Oncogene volume 35, pages 939–951 (2016)Cite this article

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Abstract

Various human malignancies are characterized by excessive activation of the Janus family of cytoplasmic tyrosine kinases (JAK) and their associated transcription factors STAT3 and STAT5. In the majority of solid tumors, this occurs in response to increased abundance of inflammatory cytokines in the tumor microenvironment prominently produced by infiltrating innate immune cells. Many of these cytokines share common receptor subunits and belong to the interleukin (IL)-6/IL-11, IL-10/IL-22 and IL-12/IL-23 families. Therapeutic inhibition of the JAK/STAT3 pathway potentially offers considerable benefit owing to the capacity of JAK/STAT3 signaling to promote cancer hallmarks in the tumor and its environment, including proliferation, survival, angiogenesis, tumor metabolism while suppressing antitumor immunity. This is further emphasized by the current successful clinical applications of JAK-specific small molecule inhibitors for the treatment of inflammatory disorders and hematopoietic malignancies. Here we review current preclinical applications for JAK inhibitors for the treatment of solid cancers in mice, with a focus on the most common malignancies emanating from oncogenic transformation of the epithelial mucosa in the stomach and colon. Emerging data with small molecule JAK-specific adenosine triphosphate-binding analogs corroborate genetic findings and suggest that interference with the JAK/STAT3 pathway may suppress the growth of the most common forms of sporadic colon cancers that arise from mutations of the APC tumor suppressor gene. Likewise inhibition of cytokine-dependent activation of the JAK/STAT3 pathway may also afford orthogonal treatment opportunities for other oncogene-addicted cancer cells that have gained drug resistance.

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Acknowledgements

The work in the authors’ laboratories is supported by the Cancer Council Victoria, grants (#1064987 and #1079257) from the National Health and Medical Research Council, Australia, by Ludwig Cancer Research and by funds from the Operational Infrastructure Support Program provided by the Victorian Government, Australia.

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Authors and Affiliations

  1. Department of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, Victoria, Australia

    M Buchert, C J Burns & M Ernst

  2. Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Austin Health, Heidelberg, Victoria, Australia

    M Buchert & M Ernst

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  1. M Buchert
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Correspondence to M Buchert or M Ernst.

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Competing interests

Matthias Ernst and Michael Buchert have filed a patent application on the use of Jak inhibitors for the treatment of colon cancer, and Chris Burns is an inventor on several patents describing Jak inhibitors.

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Buchert, M., Burns, C. & Ernst, M. Targeting JAK kinase in solid tumors: emerging opportunities and challenges. Oncogene 35, 939–951 (2016). https://doi.org/10.1038/onc.2015.150

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