MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors.

Abstract

Neurofibromatosis type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating the effects of hyperactive Ras in NF1 tumors are unknown. We performed cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs and identified global negative feedback of genes that regulate Ras/Raf/MEK/ERK signaling in both species. Nonetheless, ERK activation was sustained in mouse and human neurofibromas and MPNST. We used a highly selective pharmacological inhibitor of MEK, PD0325901, to test whether sustained Ras/Raf/MEK/ERK signaling contributes to neurofibroma growth in a neurofibromatosis mouse model (Nf1(fl/fl);Dhh-Cre) or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in more than 80% of mice tested. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide a strong rationale for testing MEK inhibitors in NF1 clinical trials.

• Authors: Walter J Jessen, Shyra J Miller, Edwin Jousma, Jianqiang Wu, Tilat A Rizvi, Meghan E Brundage, David Eaves, Brigitte Widemann, Mi-Ok Kim, Eva Dombi, Jessica Sabo, Atira Hardiman Dudley, Michiko Niwa-Kawakita, Grier P Page, Marco Giovannini, Bruce J Aronow, Timothy P Cripe, Nancy Ratner
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 123 Issue 1 Pg. 340-7 (Jan 2013) ISSN: 1558-8238 [Electronic] United States
• PMID: 23221341 (Publication Type: Clinical Trial, Journal Article, Research Support, American Recovery and Reinvestment Act, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Benzamides
• mirdametinib
• Diphenylamine
• raf Kinases
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinase Kinases
• Oncogene Protein p21(ras)

Topics

• Animals
• Benzamides (pharmacology)
• Child
• Child, Preschool
• Diphenylamine (analogs & derivatives, pharmacology)
• Extracellular Signal-Regulated MAP Kinases (genetics, metabolism)
• Female
• Humans
• Male
• Mice
• Mice, Mutant Strains
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, genetics, metabolism)
• Neoplasm Transplantation
• Neurofibromatosis 1 (drug therapy, enzymology, genetics, pathology)
• Oncogene Protein p21(ras) (genetics, metabolism)
• Peripheral Nervous System Neoplasms (drug therapy, enzymology, genetics, pathology)
• Transcriptome (drug effects, genetics)
• Transplantation, Heterologous
• Xenograft Model Antitumor Assays
• raf Kinases (genetics, metabolism)