TYK2 Cancer!1 Aug 2019 10:57
Promising New TYK2 Cancer Research, 18th June 2019!
TYK2 promotes malignant peripheral nerve sheath tumor progression through inhibition of cell death
Background
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that arise most commonly in the setting of the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome. Despite aggressive multimodality therapy, outcomes are dismal and most patients die within 5 years of diagnosis. Prior genomic studies in our laboratory identified tyrosine kinase 2 (TYK2) as a frequently mutated gene in MPNST. Herein, we explored the function of TYK2 in MPNST pathogenesis.
Methods
Immunohistochemistry was utilized to examine expression of TYK2 in MPNSTs and other sarcomas. To establish a role for TYK2 in MPNST pathogenesis, murine and human TYK2 knockdown and knockout cells were established using shRNA and CRISPR/Cas9 systems, respectively.
Results
We have demonstrated that TYK2 was highly expressed in the majority of human MPNSTs examined. Additionally, we demonstrated that knockdown of Tyk2/TYK2 in murine and human MPNST cells significantly increased cell death in vitro. These effects were accompanied by a decrease in the levels of activated Stats and Bcl-2 as well as an increase in the levels of Cleaved Caspase-3. In addition, Tyk2-KD cells demonstrated impaired growth in subcutaneous and metastasis models in vivo.
Conclusion
Taken together, these data illustrate the importance of TYK2 in MPNST pathogenesis and suggest that the TYK2 pathway may be a potential therapeutic target for these deadly cancers.
Despite this fact, there was a very significant decrease in tumor burden, suggesting that there may be other cell death mechanisms at play in addition to apoptotic cell death. Nonetheless, the mice injected with Tyk2-deficient cells exhibited less weight loss and had an increased overall survival, further supporting targeting this pathway in MPNSTs. Future studies will be aimed at better understanding the mechanisms at play in vivo. As we move forward with evaluating this pathway as a viable therapeutic target, another important aspect of TYK2 signaling that cannot be ignored is that TYK2 does not act alone, but is rather in a receptor complex in which either JAK1 or JAK2 is also involved. Thus, drug development strategies will benefit from understanding which of the other JAK family members are important in MPNST biology. Future work will be aimed at identifying the most effective inhibitor from in vitro studies and then evaluating the in vivo efficacy of the most promising TYK2 inhibitors to test as a single agent and in combination therapies.
https://onlinelibrary.wiley.com/doi/pdf/10.1002/cam4.2386
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