Preclinical Assessment of MEK Inhibitors for Malignant Peripheral Nerve Sheath Tumors Reveals Differences in Efficacy and Adaptive Response

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft-tissue sarcomas refractory to standard therapies. Inactivation of NF1 and subsequent upregulation of RAS/RAF/MEK/ERK signaling exist in the majority of MPNSTs. However, the lack of preclinical assessment of MEK inhibitors in MPNSTs hinders the clinical application as well as the development of combination therapy. To guide further clinical studies, we evaluated different MEK inhibitors in terms of efficacy, safety, and mechanism of adaptive response in treating MPNSTs. Using a MPNST tissue microarray, we found that p-ERK could serve as a biomarker for predicting the prognosis of MPNST patients as well as an effective therapeutic target. Through in vitro and in vivo experiments, we identified trametinib as the most potent MEK inhibitor for the treatment of MPNSTs. Mechanistically, reduced reactivation of the MAPK pathway and compensatory activation of the parallel pathways contributed to better efficacy. Our results provide a basis for the further clinical application of MEK inhibitors as single agents or combinational therapies.

Sporadic Metastatic Malignant Peripheral Nerve Sheath Tumour with an NF1 Mutation Responding to Trametinib: A Case Report

“…Pre-clinical mouse models demonstrated the biological rationale for MEKi in NF1-mutated MPNSTs [10, 11]. A phase 1 trial of selumetinib in 24 paediatric patients albeit with neurofibromatosis-related disease demonstrated an objective response in 71% [12].…”

Children's Oncology Group's 2023 blueprint for research: Soft tissue sarcomas

“…[77][78][79][80] In MPNST, MEK inhibitors have demonstrated antitumor effects in preclinical models that can be explored in future trials. 81 In adults with metastatic/refractory SS, adoptive T-cell therapy targeting NY-ESO-1 or MAG-A4, cancer testis antigens, has yielded durable disease control rates and will soon be studied in the pediatric setting. 82,83 Analysis of the diagnostic and prognostic significance of ctDNA for patients treated on ARST1321 is underway.…”

“…Tyrosine kinases are expressed in many NRSTS, and their inhibition has revealed antitumor effects in preclinical and clinical studies 77–80 . In MPNST, MEK inhibitors have demonstrated antitumor effects in preclinical models that can be explored in future trials 81 . In adults with metastatic/refractory SS, adoptive T‐cell therapy targeting NY‐ESO‐1 or MAG‐A4, cancer testis antigens, has yielded durable disease control rates and will soon be studied in the pediatric setting 82,83 …”