Mechanisms of Resistance to MEK Inhibitors (RAS–MAPK Pathway) in Malignant Peripheral Nerve Sheath Tumors and Their Precursor Lesions (Plexiform Neurofibromas) Associated with Neurofibromatosis Type 1

Background/Objectives: MEK inhibitors (selumetinib, mirdametinib) are the only approved class of targeted therapy for neurofibromatosis type 1 (NF1)-associated plexiform neurofibroma (PN), producing partial responses in a substantial proportion of patients (up to 63.6% in adults; objective response rate 19.7% versus 5.4% with placebo in the KOMET trial). Responses, however, are rarely complete or durable, and in malignant peripheral nerve sheath tumor (MPNST) single-agent MEK inhibition is clinically ineffective. Mechanisms of escape from MEK inhibition in these tumors remain poorly characterized and are reported in the literature as isolated primary studies without an integrative analysis. The aim of this review was to systematize both the established molecular mechanisms of resistance to MEK inhibitors in PN and MPNST and the biologically plausible candidate mechanisms extrapolated from other RAS-driven malignancies. Methods: This is a narrative review. A structured search was performed in PubMed, PubMed Central, NCBI Bookshelf, and Scopus, supplemented by clinical practice guidelines and regulatory documents; it covered publications up to 31 May 2026 and was updated in August 2026. Ninety-six sources are cited, and their composition by publication type is reported; record counts at the intermediate screening steps were not maintained, and no PRISMA flow diagram is presented. Results: Mechanisms were classified within a convergent framework into six categories: reactivation of MAPK signaling within the cascade; parallel (bypass) reactivation through receptor tyrosine kinases and adjacent inputs; epigenetic and transcriptional rewiring; cell survival programs; the tumor microenvironment and immune evasion; and intratumoural heterogeneity. Each mechanism was then graded along two independent axes—the strength of evidence that it confers resistance in PN or MPNST (E1–E3) and its therapeutic tractability (T1–T3)—and annotated with the entity and model constituting its evidence source. Conclusions: Resistance to MEK inhibition in PN and MPNST is convergent rather than mechanism-unique. The principal limitation of the field is the near-absence of clinical resistance data from patients progressing on MEK inhibitors; prospective molecular monitoring, rational combination trials, and mechanism-stratifying biomarkers are the priorities.