Selumetinib normalizes Ras/MAPK signaling in clinically relevant neurofibromatosis type 1 minipig tissues in vivo

Abstract

BACKGROUND The MEK1/2 inhibitor selumetinib was recently approved for Neurofibromatosis type 1 (NF1)-associated plexiform neurofibromas, but outcomes could be improved and its pharmacodynamic evaluation in other relevant tissues is limited. The aim of this study was to assess selumetinib tissue pharmacokinetics and pharmacodynamics using a minipig model of NF1. METHODS Eight wild type (WT) and eight NF1 +/- (NF1) minipigs received a single oral dose of 7.3 mg/kg selumetinib. Peripheral blood mononuclear cells (PBMCs), cerebral cortex, optic nerve, sciatic nerve, and skin were collected for pharmacokinetic analysis and pharmacodynamic analysis of extracellular regulated kinase phosphorylation (p-ERK) inhibition and transcript biomarkers (DUSP6 & FOS). RESULTS Key selumetinib pharmacokinetic parameters aligned with those observed in human patients. Selumetinib concentrations were higher in CNS tissues from NF1 compared to WT animals. Inhibition of ERK phosphorylation was achieved in PBMCs (mean 60% reduction), skin (95%) and sciatic nerve (64%) from all minipigs, whereas inhibition of ERK phosphorylation in cerebral cortex was detected only in NF1 animals (71%). Basal p-ERK levels were significantly higher in NF1 minipig optic nerve compared to WT and were reduced to WT levels (60%) with selumetinib. Modulation of transcript biomarkers was observed in all tissues. CONCLUSIONS Selumetinib reduces MAPK signaling in tissues clinically relevant to NF1, effectively normalizing p-ERK to WT levels in optic nerve but resulting in abnormally low levels of p-ERK in the skin. These results suggest that selumetinib exerts activity in NF1-associated central nervous system tumors by normalizing Ras/MAPK signaling and may explain common MEK inhibitor-associated dermatologic toxicities.

Spontaneous and Engineered Large Animal Models of Neurofibromatosis Type 1

“…Single-dose PK of PD0325901 showed a similar PK profile to NF1 patients in clinical trials and exhibited a robust PD effect in PBMCs isolated from treated minipigs [29]. Selumetinib, the first FDA-approved therapy for NF1, was also evaluated in NF1 +/R1947X and WT littermates, and plasma PK and PD profiles of selumetinib aligned with those of NF1 patients [90,[110][111][112][113]. We also had the unique opportunity to evaluate the pharmacology of selumetinib in tissues clinically relevant to NF1, including cerebral cortex, optic nerve, sciatic nerve, and skin.…”

“…We also had the unique opportunity to evaluate the pharmacology of selumetinib in tissues clinically relevant to NF1, including cerebral cortex, optic nerve, sciatic nerve, and skin. Selumetinib was detectable in all tissues within two hours of oral administration, and significant inhibition of p-ERK was observed in skin and sciatic nerve from all minipigs [110]. Interestingly, basal p-ERK levels were significantly higher in NF1 +/R1947X minipig optic nerve compared to WT, which were efficiently reduced to WT levels with selumetinib [110].…”

Evaluation of NF1 and RASA1 gene expression in endometriosis

“…NF1 (encoding the neurofibromin protein 1) is the major mutated gene in the germline of patients with neurofibromatosis type 1, which disrupts the regulation of the RAS / MAPK pathway [32] . Studies have shown that people with the disease with NF1 loss-of-function mutation, have a 5 times higher risk of breast cancer than the general population [33] .…”

Neurodevelopmental disorders, immunity, and cancer are connected

“…NF1 provides a remarkable recent example. After a series of clinical trials, phase II registration trial of the MEK inhibitor selumetinib ( ClinicalTrials.gov, 2021 ; Herrick et al., 2021 ; Klesse et al., 2020 ; Osum et al., 2021 ), resulted in the FDA approval of a therapy for NF1 related inoperable plexiform neurofibromas in children. MEK is a kinase in the MAPK pathway, through which NF1 signals.…”