Experimental treatment of NRAS-mutated neurocutaneous melanocytosis with MEK162, a MEK-inhibitor.
Neurocutaneous melanosis (NCM) is a rare congenital disorder characterized by the association of large and/or multiple congenital melanocytic nevi (CMN) of the skin with melanocytic lesions of the leptomeninges, including melanocytosis. Leptomeningeal melanocytosis carries a poor prognosis once neurological symptoms develop. Despite surgery, which is often not radical, few other treatment options exist. Recently, it was demonstrated that early embryonic, post-zygotic somatic mutations in the NRAS gene are implicated in the pathogenesis of NCM.In this report, we present a 13-year-old boy with NCM and progressive symptomatic leptomeningeal melanocytosis. A somatic NRASQ61K mutation was present in both CMN as well as the melanocytosis. Despite repeated surgery, the patient showed clinical progression. Therefore, treatment with MEK162, a MEK inhibitor, was started on compassionate use base. The patient died only five days later, i.e. too early to expect a clinical effect of MEK162 therapy. We therefore studied the effect of MEK162 at the protein level in the leptomeningeal tumor by immunohistochemical and Western Blot analyses using Ki67 and pERK antibodies. We observed lower MIB-1 expression and lower pERK expression in the post-treatment samples compared to pre-treatment, suggesting a potential effect of MEK inhibiting therapy. Further studies are needed to determine whether MEK inhibitors can effectively target NRAS-mutated symptomatic NCM, a rare but potentially fatal disease.
Department of Pathology, Canisius Wilhelmina Hospital, PO Box 9015, 6500 GS Nijmegen, The Netherlands. h.kusters@cwz.nl.
Heidi Vn
HV
Küsters-Vandevelde
Annelieke Ecab
AE
Willemsen
Patricia Jta
PJ
Groenen
Benno
B
Küsters
Martin
M
Lammens
Pieter
P
Wesseling
Melika
M
Djafarihamedani
Jos
J
Rijntjes
Hans
H
Delye
Michel A
MA
Willemsen
Carla Ml
CM
van Herpen
Willeke Am
WA
Blokx
D000293:Adolescent; D001562:Benzimidazoles / Q000627:therapeutic use*; D001921:Brain / Q000473:pathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008548:Melanosis / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D020752:Neurocutaneous Syndromes / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D013116:Spinal Cord / Q000473:pathology
D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; C581313:binimetinib; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human