Genomic status of MET potentiates sensitivity to MET and MEK inhibition in NF1-related malignant peripheral nerve sheath tumors
Autor: | Curt J. Essenburg, Diana M. Cardona, Jacqueline D. Peacock, Elissa Boguslawski, Vadim Khachaturov, Mary E. Winn, Flavio Maina, Rosanna Dono, Carrie R. Graveel, Mark Chen, Matthew R. Steensma, Julie Koeman, David G. Kirsch, Jamie Grit, Rebecca D. Dodd, Matthew G Pridgeon, Zachary Madaj, Megan J. Bowman, Elizabeth A. Tovar |
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Přispěvatelé: | Center for Neuroscience and Cell Biology (CNC) (CNC), University of Coimbra [Portugal] (UC)-Neuroscience Research Domain, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS) |
Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
MAPK/ERK pathway Trametinib Neurofibromatosis type I Cancer Research congenital hereditary and neonatal diseases and abnormalities business.industry MEK inhibitor [SDV]Life Sciences [q-bio] Cancer Malignant peripheral nerve sheath tumor medicine.disease 3. Good health nervous system diseases 03 medical and health sciences 030104 developmental biology Oncology medicine Cancer research business Protein kinase B neoplasms PI3K/AKT/mTOR pathway |
Zdroj: | Cancer Research Cancer Research, American Association for Cancer Research, 2018, 78 (13), pp.canres.3167.2017. ⟨10.1158/0008-5472.CAN-17-3167⟩ Cancer Research, 2018, 78 (13), pp.canres.3167.2017. ⟨10.1158/0008-5472.CAN-17-3167⟩ |
ISSN: | 0008-5472 1538-7445 |
Popis: | Malignant peripheral nerve sheath tumors (MPNST) are highly resistant sarcomas that occur in up to 13% of individuals with neurofibromatosis type I (NF1). Genomic analysis of longitudinally collected tumor samples in a case of MPNST disease progression revealed early hemizygous microdeletions in NF1 and TP53, with progressive 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 MPNSTs with MPNSTs derived from Nf1ko/+;p53R172H;Plp-creERTtg/+ (NF1-P53) and Nf1ko/+;Plp-creERTtg/+ (NF1) mice revealed unique Met, Ras, and PI3K signaling patterns. NF1-MET MPNSTs were uniformly sensitive to the highly selective MET inhibitor, capmatinib, whereas a heterogeneous response to MET inhibition was observed in NF1-P53 and NF1 MPNSTs. Combination therapy of capmatinib and the MEK inhibitor trametinib resulted in reduced response variability, enhanced suppression of tumor growth, and suppressed RAS/ERK and PI3K/AKT signaling. These results highlight the influence of concurrent genomic alterations on RAS effector signaling and therapy response to tyrosine kinase inhibitors. Moreover, these findings expand our current understanding of the role of MET signaling in MPNST progression and identify a potential therapeutic niche for NF1-related MPNSTs. Significance: Longitudinal genomic analysis reveals a positive selection for MET and HGF copy number gain early in malignant peripheral nerve sheath tumor progression. Cancer Res; 78(13); 3672–87. ©2018 AACR. |
Databáze: | OpenAIRE |
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