Targeted pharmacotherapy of NF1-associated plexiform neurofibromas: current evidence and future perspectives

Neurofibromatosis type 1 (NF1) is a common autosomal dominant tumor-predisposition syndrome caused by loss-of-function NF1 variants. Somatic inactivation of the remaining allele in Schwann cell precursors drives plexiform neurofibromas (PN), benign but often disfiguring tumors that can progress to malignant peripheral nerve sheath tumors. Driven by constitutive RAS-MAPK activation, PN are among the most pharmacologically tractable manifestations of NF1.

This review covers the pharmacotherapy of NF1-associated PN: RAS-MAPK activation in Schwann cells; the approved MEK inhibitors selumetinib, mirdametinib and luvometinib, their clinical pharmacology and the next-generation pipeline; mechanisms of MEK-inhibitor resistance; strategies targeting additional RAS-network nodes (SOS1, SHP2, mTOR) or acting independently; preclinical models; and practical considerations across pediatric and adult populations. It is based on a PubMed and ClinicalTrials.gov search (January 2010-September 2026).

MEK inhibitors have transformed PN management, but responses remain incomplete, regrowth after discontinuation is common, and optimal treatment duration is undefined. The central challenge is now to move from tumor shrinkage toward long-term disease modification while limiting chronic toxicity. Rational combinations targeting pathway reactivation offer a compelling route toward deeper, durable responses, whereas checkpoint- and stimulator of interferon genes (STING)-directed immunotherapy and gene-replacement strategies remain preclinical.