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 (PK) and pharmacodynamics (PD) using a minipig model of NF1. Methods. WT (n = 8) and NF1 (n = 8) 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 PK analysis and PD analysis of extracellular regulated kinase phosphorylation (p-ERK) inhibition and transcript biomarkers (DUSP6 & FOS). Results. Key selumetinib PK 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 CNS tumors by normalizing Ras/MAPK signaling and may explain common MEK inhibitor-associated dermatologic toxicities.
Bibliographical noteFunding Information:
We would like to acknowledge the assistance of the Clinical Pharmacology Shared Resource of the Masonic Cancer Center, a comprehensive cancer center designated by the National Cancer Institute, supported in part by P30 CA77598.
This study was supported by the National Institutes of Health [5R01NS086219, T32OD0100993 to S.H.O.]; American Cancer Society [123939 to D.A.L.]; Children’s Tumor Foundation, Synodos for NF1 (to A.L.W., D.A.L., and C.L.M.); and National Cancer Institute P30 [CA77598].
© The Author(s) 2021.
- MEK inhibitor
- neurofibromatosis type 1
PubMed: MeSH publication types
- Journal Article