Abstract
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly resistant sarcomas that occur in up to 13% of individuals with Neurofibromatosis Type 1 (NF1). Genomic analysis of longitudinally collected tumor samples in a case of MPNST disease progression revealed early hemizygous microdeletions in NF1 and TP53, with concomitant amplifications of MET, HGF, and EGFR. To examine the role of MET in MPNST progression, we developed mice with enhanced MET expression and NF1 ablation (NF1fl/KO;lox-stop-loxMETtg/+;Plp-creERTtg/+; referred to as NF1-MET). NF1-MET mice express a robust MPNST phenotype in the absence of additional mutations. A comparison of NF1-MET MPSNTs with MPNSTs derived from NF1KO/+;p53R172H;Plp-creERTtg/+ (NF1-P53) and NF1KO/+;Plp-creERTtg/+ (NF1) mice revealed unique Met, Ras, and PI3K signaling patterns. To investigate the therapeutic potential of MET inhibition among tumorgrafts derived from the respective MPNST models, we tested the highly selective MET inhibitor, capmatinib. NF1-MET MPNSTs were uniformly sensitive to MET inhibition whereas only a small subset of NF1-P53 and NF1 MPNSTs were inhibited. These results confirm that MET activation is sufficient for Schwann cell dedifferentiation into MPNSTs in the context of NF1 deficiency. RAS-MET signal interactions may be an important driver of MPSNT disease progression.
Footnotes
Funding The Neurofibromatosis Therapeutic Acceleration Program (NTAP), The Johns Hopkins University (JHU), and the Van Andel Institute.
Conflict of interest The authors have declared that no conflict of interest exists.