Targeting RAS/MAPK Signaling: MEK Inhibitors as Breakthrough Therapy for NF1-Associated Plexiform Neurofibroma- A Review
Year: 2025
Type: article
Study design: Systematic Review
Abstract: — Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder resulting from NF1 gene mutations that cause constitutive activation of the RAS/MAPK signaling pathway. This dysregulation promotes the development of plexiform neurofibromas (PNs), benign tumors associated with notable morbidity when inoperable. This review summarizes advances in novel targeted therapies of NF1-associated PNs, focusing on MEK inhibitors with emphasis on selumetinib and mirdametinib. A systematic literature search was performed using PubMed, ResearchGate, and Google Scholar for studies published up to July 2025, complemented by manual reference screening. MEKis suppress MEK1/2 activity, thereby attenuating aberrant RAS/MAPK signaling and tumor growth. Selumetinib, approved by the U.S. Food and Drug Administration (FDA) in 2020 for pediatric NF1-PNs, achieved a ≥20% tumor volume reduction in 74% of patients and yielded significant improvements in pain and quality of life. Mirdametinib, approved in 2025 for both pediatric and adult populations, demonstrated a median 41% tumor reduction and sustained symptomatic benefit. The principal toxicities included dermatologic, gastrointestinal, ocular, and cardiac events, generally manageable with dose adjustment and monitoring. Despite substantial clinical benefit, unresolved challenges include long-term safety, optimal dosing, and the integration of MEK inhibition with surgical and multimodal approaches. Future research should focus on combination therapies and refinement of individualized treatment strategies. MEK inhibitors represent a major therapeutic breakthrough for NF1-associated PNs, offering durable tumor control, functional improvement, and new opportunities for precision medicine in neurofibromatosis care. Keywords— neurofibromatosis, neurofibromatosis type 1, NF1, plexiform neurofibroma, MEK inhibitors; targeted therapy, selumetinib, mirdametinib
Authors: Martyna Nowak, Daria Podleśna, Nicola Stencel, Gabriela Majta, Mateusz Witowicz, Konrad Krupa, Katarzyna Kilarowska, Aleksandra Machnik, Aleksander Tuleja, Jakub Rudzki
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7107944802
FWCI:
Cites:
Cited by:
Related to: