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Kim et al. Rare Dis Orphan Drugs J. 2026;5:6 Page 3 of 8

Figure 1. Mechanism of MEK inhibition by selumetinib and mirdametinib. Loss of NF1 function leads to overactive Ras signaling, promoting
tumor growth. Created in BioRender. Kim, H. (2025) https://BioRender.com/796ondy. NF1: Neurofibromatosis type 1; MEK 1/2:
mitogen-activated protein kinase kinase; ERK: extracellular signal-regulated kinase.

APPROVED MEK INHIBITORS
The emergence of MEK1/2 inhibitors, selumetinib and mirdametinib, has led to Food and Drug
Administration (FDA)-approved therapies for patients with symptomatic, inoperable PNs [Table 1] [9,10] .
MEK inhibitors are allosteric inhibitors of MEK1 and MEK2. MEK1/2 function within the mitogen-activated
protein kinase (MAPK) signaling cascade, referred to as the Rat sarcoma (RAS)-rapidly accelerated
fibrosarcoma (RAF)-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase
(ERK) pathway, which regulates cellular growth, differentiation, proliferation, and survival [Figure 1] [9,11] . In
NF1, Ras signaling becomes dysregulated due to loss or reduced activity of neurofibromin, leading to
prolonged and uncontrolled downstream MAPK activation and growth of peripheral nerve sheath tumors in
some individuals. By inhibiting MEK1/2, selumetinib and mirdametinib prevent downstream activation of
ERK, thereby suppressing cell proliferation and angiogenesis and producing tumor shrinkage and disease
stabilization [9,11] .

Selumetinib (Koselugo), approved on April 10, 2020, was the first FDA-approved therapy for PNs for
pediatric patients ≥ 2 years with symptomatic, inoperable PNs [Table 1] . The approval was based on results
[9]
from the Phase II SPRINT trial (NCT01362803), in which 70% of the patients achieved partial response,
defined as a ≥ 20% reduction in tumor volume on volumetric magnetic resonance imaging (MRI), with the
median tumor volume-reduction of 27.9% [9,12] . Notably, 56% of participants had a durable response lasting
≥ 12 cycles (approximately 1 year) . Progression-free survival at 3 years was substantially higher in patients
[12]
taking selumetinib compared with a matched natural-history cohort from the National Cancer Institute
(NCI), in which 78% of untreated individuals had ≥ 20% tumor growth with median progression-free
survival of 1.3 years . In addition to tumor shrinkage, there were clinically meaningful improvements in
[12]