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 ~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 secondary to radiation therapy. In the setting of NF1, MPNST arise from malignant transformation of a benign precursor lesion, a plexiform neurofibroma. Despite aggressive therapy, the recurrence rate is high and the vast majority of people with these cancers will die within 5 years of diagnosis. Given limited treatment options, there is a pressing need to identify novel therapeutic targets. Our laboratory previously 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 increased cell death in vitro and decreased tumor growth. Here, immunohistochemistry (IHC) shows strong TYK2 staining in 63/112 (56%) MPNST, 13/39 (33%) plexiform neurofibromas and 23/24 (96%) atypical neurofibromas (ANNUBP).In murine MPNST JW23.3 cells, knockout of TYK2 and TYK2/STAT3 markedly block proliferation, while STAT3 knockout only modestly reduces proliferation, as assessed by IncuCyte live cell assays. Similarly, pharmacologic inhibition of TYK2, STAT3and Bcl2 dose-dependently decreased proliferation and induced apoptosis over time. RNAseq pathway analysis on TYK2inhibitor 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 increasedpERK1/2 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2023
- Accession Number
- AD1196263
Entities
People
- Angela Hirbe
Organizations
- Washington University in St. Louis