Selumetinib: the first ever approved drug for neurofibromatosis-1 related inoperable plexiform neurofibroma

Plexiform neurofibroma (PN) is one of the most striking clinical features of neurofibromatosis 1. Growth of PN can occur at any stage of life but mostly in childhood and during hormonal changes. They arise from multiple nerve fascicles and may transform into malignant peripheral nerve sheath tumors. There was previously no approved medical therapy for tumor shrinkage or regression. Surgery is not always possible due to inaccessible location, involvement of vital tissue, optimal timing, and incomplete removal. Recently, the US Food and Drug Administration approved selumetinib for pediatric patients, 2 years of age and older, with neurofibromatosis type 1 who have symptomatic, inoperable tumor. Neurofibromin, a 2818 amino acid long cytoplasmic protein, is the product of the NF1 gene. It inhibits the activity of Ras GTPase proteins. Lack of functional neurofibromin in patients with NF1 leads to dysregulated Ras and tumorigenesis. RAS MAPK pathway is hyper activated in NF1. Selumetinib is an inhibitor of MEK1 and MEK2 proteins, which play an important role in the MAPK signaling pathway related to tumor growth. Approval was based on one pivotal, single-arm, phase II trial. 70% of participants experienced confirmed partial response of tumor shrinkage, and 68% also had improvement of related complications, and other studies have also shown beneficial responses. The major limitation of this molecule regarding its mechanism of action is the dose-dependent effect of MEK inhibition in growth of neurofibroma. Long-term safety and efficacy studies are to be done in the future to establish selumetininb as a useful medicine.