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

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 (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.

Kinome Profiling of NF1-Related MPNSTs in Response to Kinase Inhibition and Doxorubicin Reveals Therapeutic Vulnerabilities

“…This study revealed the early concomitant presence of MET, HGF, and EGFR amplifications, as well as the site-specific expansion of these loci over time and treatment. These data point to an adaptive mechanism involving RTK signaling for both malignant transformation and clonal selection in MPNSTs [6]. To advance our understanding of the MPNST therapeutic response and resistance to RAS pathway inhibition, we developed diverse preclinical NF1-related MPNST models, including an "MET-addicted" model of NF1-related MPNSTs (NF1-MET), an Nf1/Trp53-deficient model (NF1-P53), and an NF1 model (P53 WT , Hgf -amplified) [7][8][9].…”

“…Kinome reprogramming can be heavily influenced by genomic alterations (i.e., amplification and mutation) of kinases, the overexpression of other kinases, or ligand activation [13][14][15][16]. Our genomic analysis of MPNST progression identified genomic events during human MPNST progression that heighten RTK signaling, AKT/mTOR activation, and cell survival [6]. To understand how these genomic contexts influence the therapy response to kinase inhibition, we conducted a phosphoproteomic analysis using a reverse phase protein array (RPPA) in our established MPNST mouse models.…”

“…To advance our understanding of the MPNST therapeutic response and resistance to RAS pathway inhibition, we developed diverse preclinical NF1-related MPNST models, including an "MET-addicted" model of NF1-related MPNSTs (NF1-MET), an Nf1/Trp53-deficient model (NF1-P53), and an NF1 model (P53 WT , Hgf -amplified) [7][8][9]. Using these MPNST models, we determined that P53 deficiency significantly exacerbates resistance to MEK inhibition; however, combined MEK and MET inhibition overcame therapy resistance [6]. Importantly, these results demonstrated that NF1-related MPNSTs maintain multiple signaling dependencies beyond RAS, and that genomic determinants, such as P53 and RTK genomic alterations, profoundly influence the therapy response.…”

Integrative analysis identifies candidate tumor microenvironment and intracellular signaling pathways that define tumor heterogeneity in NF1

“…For example, genomic approaches were recently used to identify the loss of function of polycomb repressor 2 complex components EED or SUZ12 , alongside CDKN2A and NF1 mutations as crucial co-mediators of MPNST transcriptional dysregulation, pathogenesis, and sensitivity to BRD4 inhibitors [9,11] . Others using genomic approaches to explore nerve sheath tumor biology identified MET and HGF amplification in MPNSTs; furthermore, models of MET amplified MPNSTs were subsequently sensitive to the MET inhibitor capmatinib [7] . Transcriptomics-focused approaches have also identified molecular features like MEK signaling, type 1 interferon signaling, and Aurora kinase A as putative therapeutic targets in NF1 tumors [12][13][14] .…”

“…Others using genomic approaches to explore nerve sheath tumor biology identified MET and HGF amplification in MPNSTs. Furthermore, models of MET-amplified MPNSTs were subsequently sensitive to the MET inhibitor capmatinib [7]. Transcriptomics-focused approaches have also identified molecular features like MEK signaling, type 1 interferon signaling, and Aurora kinase A as putative therapeutic targets in NF1 tumors [12][13][14].…”