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Comprehensive evaluation of MEK inhibitors for malignant peripheral nerve sheath tumors reveals differences in efficacy and drug resistance development

ABSTRACT: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas which lack effective drugs. Previous studies support the usefulness of MEK inhibitors (MEKis) for treating RAS-driven tumors, however, the lack of preclinical assessment of MEK inhibitors in MPNSTs limit the clinical application as well as the development of combination therapy. In this study, we comprehensively evaluated 8 MEK inhibitors in terms of efficiency, safety and mechanisms of resistance for treating MPNSTs. We identified the most promising MEK inhibitor, trametinib, for the treatment of MPNSTs. Through high-throughput transcriptomic sequencing and drug screening, we discovered the upregulation of integrin signaling contributing to MEK inhibitor resistance, termed as cell adhesion-mediated drug resistance (CAM-DR). We also confirmed MET overactivation in MEKi-resistant MPNST cells. These targets are potential solutions to overcome MEKi- resistance in clinical applications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE174100 | GEO | 2022/07/26

REPOSITORIES: GEO

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Project description:Background: Malignant peripheral nerve sheath tumors (MPNST) are soft-tissue sarcomas that can arise either sporadically or in association with neurofibromatosis type 1 (NF1). These aggressive malignancies confer poor survival, with no effective therapy available. Methods: We generated five patient-derived MPNST orthoxenograft models (three NF1-related and two sporadic) and performed an exhaustive histological and molecular characterization of primary MPNSTs and their corresponding orthoxenografts. Finally, orthoxenografts models were used as an in vivo pre-clinical platform to test several treatment strategies. Results: MPNST orthoxenografts recapitulate the histopathological properties and preserve the genomic and transcriptomic status of their parental primary tumors. Additionally, they mimic distal dissemination properties in mice. Compatible with an origin in a catastrophic event and subsequent stabilization, MPNSTs contained highly altered genomes that remained remarkably stable in orthoxenograft establishment and along passages. Although preliminary, the results presented here point to clear differences between NF1-associated and sporadic MPNSTs. In accordance, mutation frequency in sporadic MPNSTs was an order of magnitude higher than in NF1-associated MPNSTs and unsupervised cluster analysis and principal component analysis (PCA) using a MPNST signature perfectly divided the samples between NF1 and sporadic MPNST. Finally, different therapeutic approaches tested in the validated orthoxenograft MPNST models, reveal that sorafenib, or in combination with doxorubicin or rapamycin caused a great tumor reduction in all models. Conclusion: The development of a well-characterized and standardized preclinical model for MPNSTs has laid the foundations for evaluating novel therapeutic strategies in the clinical setting. Moreover, results obtained strongly support the clinical evaluation of Sorafenib in this subset of patients. Primary MPNSTs were implanted in the sciatic nerve of nude mices to create orthoxenograft MPNST models. Several orthoxenograft passages were created. The primary tumor (when available) and passages 1 and 4 were selected for gene expression profiling to demonstrate that the orthoxenografts closely resemble their primary tumors and are stable along xenograft passages.

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Comprehensive evaluation of MEK inhibitors for malignant peripheral nerve sheath tumors reveals differences in efficacy and drug resistance development

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