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Cancer Res. 2018 Jul 1;78(13):3672-3687. doi: 10.1158/0008-5472.CAN-17-3167. Epub 2018 May 2.

Genomic Status of MET Potentiates Sensitivity to MET and MEK Inhibition in NF1-Related Malignant Peripheral Nerve Sheath Tumors.

Author information

1
Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan.
2
College of Health Professions, Ferris State University, Big Rapids, Michigan.
3
Spectrum Health System, Helen DeVos Children's Hospital, Grand Rapids, Michigan.
4
Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, Michigan.
5
Genomics Core, Van Andel Research Institute, Grand Rapids, Michigan.
6
Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
7
Department of Pathology, Duke University Medical Center, Durham, North Carolina.
8
Department Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina.
9
Aix-Marseille Univ, CNRS, IBDM, Marseille, France.
10
Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan. Matt.Steensma@vai.org.
11
Michigan State University College of Human Medicine, Grand Rapids, Michigan.
#
Contributed equally

Abstract

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.

PMID:
29720369
PMCID:
PMC6235171
DOI:
10.1158/0008-5472.CAN-17-3167
[Indexed for MEDLINE]
Free PMC Article

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