TYK2 in Cancer Metastases: Genomic and Proteomic Discovery

SIMPLE SUMMARY: Cancer deaths are predominantly due to metastases rather than the primary tumors, and thus there is an urgent need for the discovery of more effective drug therapies for metastatic cancer. Recent genomics, transcriptomics, and proteomics studies have identified tyrosine kinase 2 (TYK2) as an oncogene that is frequently mutated or overexpressed in many types of cancer and metastases. A member of the Janus kinase (JAK) family, TYK2 mediates the signals of numerous cytokines involved in immune and inflammatory signaling. In cancer cells, activation of TYK2 can lead to decreased cell death as well as increased cell growth and invasion. Multiple drugs that specifically block TYK2 or JAKs are currently FDA-approved or in clinical trials. In this review, we provide an overview of the screening, molecular, and animal studies that have characterized the role of TYK2 in cancer and metastases, and the potential of TYK2 inhibitors as effective cancer therapies. ABSTRACT: 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.