Neurofibromatosis type 1 (NF1) is an autosomal dominant multisystem disorder caused by germline mutations in the NF1 gene, classified as a RASopathy. The NF1 gene encodes neurofibromin, a RAS GTPase-activating protein that modulates the Ras-MAPK signaling cascade. MEK1 inhibitors targeting the Ras-MAPK pathway were initially developed for cancer treatment and have since expanded their applications to RASopathies due to shared molecular mechanisms. Following the FDA approval of MEK1 inhibitor selumetinib for NF1-associated plexiform neurofibromas, drug development has focused on combination therapies, multi-pathway targeting, AI-driven drug discovery, preclinical models, and orphan drug designation to address a broad spectrum of NF1-associated tumors and conditions. Over the past 30 years, significant progress has been made in understanding NF1. This review aims to summarize recent research advancements that enhance the development of NF1 therapeutics, addressing existing gaps in current knowledge and treatment strategies. Ultimately, this could promote personalized medicine, tailoring treatments to the unique genetic and tumor microenvironmental characteristics of each NF1 patient.
Introduction
FDA-approved Selumetinib and Investigational Mirdametinib: A New Era in NF1-PN Treatment
Genotype-phenotype Correlations in NF1
Mosaic Neurofibromatosis and Loss of Heterozygosity
NF1+/- Tumor Microenvironment
Functional Differences in GAP Activity of NF1 Isoforms: The Role of Exon 23a
Conclusion
Acknowledgements
Funding
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