TYK2 as a Biomarker and Therapeutic Target for NF1-Associated Malignant Peripheral Nerve Sheath Tumors

ABSTRACT

Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas that account for approximately 5% of all soft tissue sarcomas. These tumors occur at an increased frequency in patients with the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome, but also occur sporadically or as a secondary complication of radiation therapy. In the setting of NF1, MPNST arise from malignant transformation of a benign precursor lesion, a plexiform neurofibroma. Initial treatment for MPNST typically involves surgery and radiation with or without chemotherapy. However, despite aggressive therapy, the recurrence rate is high and the vast majority of people with these cancers will die within 5 years of diagnosis. Treatment for metastatic disease is limited to cytotoxic chemotherapy and clinical trials. As such, there is a pressing need to identify novel therapeutic targets. Prior work from our laboratory identified TYK2 as a gene mutated in a subset of MPNSTs. More recently, we have shown that genetic knockdown of TYK2 in both human and murine MPNST cell lines results in decreased tumor growth and increased cell death in vitro. Additionally, genetic knockdown of Tyk2 in murine MPNST cells resulted in decreased tumor burden in subcutaneous tumors and metastatic tumor models. Immunohistochemistry (IHC) for TYK2 was performed on 27 MPNST and 16 plexiformneurofibromas to evaluate TYK2 association with tumor type, overall survival, metastasis and therapeutic response. Additionally, similar to genetic knockdown, pharmacologic inhibition of TYK2 dose-dependently decreased the percent cell confluence and induced apoptosis over time in four MPNST cell-lines, as assessed by IncuCyte proliferation and apoptosis assays. In murine MPNST JW23.3 cells, incubation with TYK2 inhibitors reduced pSTAT3 levels, but not pERK or pS6K.