Advances in genomic analysis and proteomic tools have rapidly expanded identification of biomarkers and molecular targets important to cancer development and metastasis. On an individual basis, personalized medicine approaches allow better characterization of tumors and patient prognosis, leading to more targeted treatments by detection of specific gene mutations, overexpression, or activity. Genomic and proteomic screens by our lab and others have revealed tyrosine kinase 2 (TYK2) as an oncogene promoting progression and metastases of many types of carcinomas, sarcomas, and hematologic cancers. TYK2 is a Janus kinase (JAK) that acts as an intermediary between cytokine receptors and STAT transcription factors. TYK2 signals to stimulate proliferation and metastasis while inhibiting apoptosis of cancer cells. This review focuses on the growing evidence from genomic and proteomic screens, as well as molecular studies that link TYK2 to cancer prevalence, prognosis, and metastasis. In addition, pharmacological inhibition of TYK2 is currently used clinically for autoimmune diseases, and now provides promising treatment modalities as effective therapeutic agents against multiple types of cancer.

Purpose: Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited treatment options and poor survival rates. About half of MPNST cases are associated with the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome. Overexpression of TYK2 occurs in the majority of MPNST implicating TYK2 as a therapeutic target. Experimental Design: The effects of pharmacologic TYK2 inhibition on MPNST cell proliferation and survival were examined using IncuCyte live cell assays in vitro, and downstream actions were analyzed using RNAseq, qPCR arrays, and validation of protein changes with the WES automated western system. Inhibition of TYK2 alone and in combination with MEK inhibition was evaluated in vivo using both murine and human MPNST cell lines, as well as MPNST PDX. Results: Pharmacologic inhibition of TYK2 dose-dependently decreased proliferation and induced apoptosis over time. RNAseq pathway analysis on TYK2 inhibitor treated MPNST demonstrated decreased expression of cell cycle, mitotic, and glycolysis pathways. TYK2 inhibition resulted in upregulation of the MEK/ERK pathway gene expression, by both RNA-seq and qPCR array as well as increased pERK1/2 levels by WES Western system. The compensatory response was tested with dual treatment with TYK2 and MEK inhibitors, which synergistically decreased proliferation and increased apoptosis in vitro. Finally, combination therapy was shown to inhibit growth of MPNST in multiple in vivo models. Conclusions: These data provide the preclinical rationale for the development of a phase 1 clinical trial of deucravacitinib and mirdametinib in NF1-assosciated MPNST.

<div>AbstractPurpose:<p>Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited treatment options and poor survival rates. About half of MPNST cases are associated with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Overexpression of TYK2 occurs in the majority of MPNST, implicating TYK2 as a therapeutic target.</p>Experimental Design:<p>The effects of pharmacologic TYK2 inhibition on MPNST cell proliferation and survival were examined using IncuCyte live cell assays <i>in vitro</i>, and downstream actions were analyzed using RNA-sequencing (RNA-seq), qPCR arrays, and validation of protein changes with the WES automated Western system. Inhibition of TYK2 alone and in combination with MEK inhibition was evaluated <i>in vivo</i> using both murine and human MPNST cell lines, as well as MPNST PDX.</p>Results:<p>Pharmacologic inhibition of TYK2 dose-dependently decreased proliferation and induced apoptosis over time. RNA-seq pathway analysis on TYK2 inhibitor–treated MPNST demonstrated decreased expression of cell cycle, mitotic, and glycolysis pathways. TYK2 inhibition resulted in upregulation of the MEK/ERK pathway gene expression, by both RNA-seq and qPCR array, as well as increased pERK1/2 levels by the WES Western system. The compensatory response was tested with dual treatment with TYK2 and MEK inhibitors, which synergistically decreased proliferation and increased apoptosis <i>in vitro</i>. Finally, combination therapy was shown to inhibit growth of MPNST in multiple <i>in vivo</i> models.</p>Conclusions:<p>These data provide the preclinical rationale for the development of a phase I clinical trial of deucravacitinib and mirdametinib in NF1-assosciated MPNST.</p></div>

<p>Supplemental Fig.S2. TYK2 inhibitors reduce proliferation and induce apoptosis in MPNST-724 cells.</p>

<p>Supplemental Fig.S3. Genetic knockout of TYK2 blocks the effects of TYK2 inhibitors on proliferation in JW23.3 cells.</p>