Genomic status of MET potentiates sensitivity to MET and MEK inhibition in NF1-related malignant peripheral nerve sheath tumors

Jacqueline D. Peacock; Matthew G. Pridgeon; Elizabeth A. Tovar; Curt J. Essenburg; Megan Bowman; Zachary Madaj; Julie Koeman; Elissa A. Boguslawski; Jamie Grit; Rebecca D. Dodd; Vadim Khachaturov; Diana M. Cardona; Mark Chen; David G. Kirsch; Flavio Maina; Rosanna Dono; Mary E. Winn; Carrie R. Graveel; Matthew R. Steensma

doi:10.1158/0008-5472.CAN-17-3167

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Genomic status of MET potentiates sensitivity to MET and MEK inhibition in NF1-related malignant peripheral nerve sheath tumors

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Genomic status of MET potentiates sensitivity to MET and MEK inhibition in NF1-related malignant peripheral nerve sheath tumors

Jacqueline D. Peacock, Matthew G. Pridgeon, Elizabeth A. Tovar, Curt J. Essenburg, Megan Bowman, Zachary Madaj, Julie Koeman, Elissa A. Boguslawski, Jamie Grit, Rebecca D. Dodd, …

Cancer research (Chicago, Ill.), Vol.78(13), pp.3672-3687

05/02/2018

DOI: 10.1158/0008-5472.CAN-17-3167

PMCID: PMC6235171

PMID: 29720369

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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 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 ( Nf1 fl/KO ;lox-stop-loxMET tg/+ ;Plp-creERT tg/+ ; 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 Nf1 KO/+ ;p53 R172H ;Plp-creERT tg/+ (NF1-P53) and Nf1 KO/+ ;Plp-creERT tg/+ (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.

capmatinib

malignant peripheral nerve sheath tumor (MPNST)

MEK

MET

NF1

trametinib

Details

Title: Subtitle: Genomic status of MET potentiates sensitivity to MET and MEK inhibition in NF1-related malignant peripheral nerve sheath tumors
Creators: Jacqueline D. Peacock - Van Andel Institute
Matthew G. Pridgeon - Helen DeVos Children's Hospital
Elizabeth A. Tovar - Van Andel Institute
Curt J. Essenburg - Van Andel Institute
Megan Bowman - Van Andel Institute
Zachary Madaj - Van Andel Institute
Julie Koeman - Van Andel Institute
Elissa A. Boguslawski - Van Andel Institute
Jamie Grit - Van Andel Institute
Rebecca D. Dodd - Duke Medical Center
Vadim Khachaturov - Helen DeVos Children's Hospital
Diana M. Cardona - Duke Medical Center
Mark Chen - Duke Medical Center
David G. Kirsch - Duke University
Flavio Maina - Aix-Marseille Université
Rosanna Dono - Aix-Marseille Université
Mary E. Winn - Van Andel Institute
Carrie R. Graveel - Van Andel Institute
Matthew R. Steensma - Van Andel Institute
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.78(13), pp.3672-3687
DOI: 10.1158/0008-5472.CAN-17-3167
PMID: 29720369
PMCID: PMC6235171
NLM abbreviation: Cancer Res
ISSN: 0008-5472
eISSN: 1538-7445
Grant note: DOI: 10.13039/100007880, name: Johns Hopkins University (JHU), award: NTAP-2014-295; DOI: 10.13039/100006019, name: Van Andel Research Institute (VARI), award: N/A
Language: English
Date published: 05/02/2018
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984359939602771

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