Genomic MET amplification occurs early in NF1-related malignant peripheral nerve sheath tumor (MPNST) progression and is a potent therapeutic target

Peacock, J. D.; Pridgeon, M. G.; Tovar, E. A.; Essenburg, C. J.; Bowman, M. J.; Madaj, Z.; Koeman, J.; Grit, J.; Dodd, R. D.; Cardona, D. M.; Chen, M.; Kirsch, D.; Maina, F.; Dono, R.; Winn, M. E.; Graveel, C. R.; Steensma, M. R.

doi:10.1101/199000

bioRxiv · 10.1101/199000

Genomic MET amplification occurs early in NF1-related malignant peripheral nerve sheath tumor (MPNST) progression and is a potent therapeutic target

Peacock, J. D.·Pridgeon, M. G.·Tovar, E. A.·Essenburg, C. J.·Bowman, M. J.·Madaj, Z.·Koeman, J.·Grit, J.·Dodd, R. D.·Cardona, D. M.·Chen, M.·Kirsch, D.·Maina, F.·Dono, R.·Winn, M. E.·Graveel, C. R.·Steensma, M. R.

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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.

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Peacock, J. D., Pridgeon, M. G., Tovar, E. A., Essenburg, C. J., Bowman, M. J., Madaj, Z., Koeman, J., Grit, J., Dodd, R. D., Cardona, D. M., Chen, M., Kirsch, D., Maina, F., Dono, R., Winn, M. E., Graveel, C. R., Steensma, M. R.. 2017-10-05. Genomic MET amplification occurs early in NF1-related malignant peripheral nerve sheath tumor (MPNST) progression and is a potent therapeutic target. https://doi.org/10.1101/199000

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