MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors
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
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
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Research Article

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 (Nf1fl/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

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Figure 2

PD0325901 inhibits neurofibroma growth.

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PD0325901 inhibits neurofibroma growth. (A–F) Serial MRI in Nf1flox/flox...
(A–F) Serial MRI in Nf1flox/flox;Dhh-Cre mice given vehicle (A–C) versus 10 mg/kg PD0325901 (D–F). MRI was conducted on 5-month-old pretreated mice (A and D) at treatment onset (B and E, day 0; 7 months old), and at the end of treatment (C and F, day 60; 9 months old). Images show representative tumor-bearing mice given vehicle control (A–C) or PD0325901 (D–F). Note the reduction in size and intensity of bright bilateral neurofibromas treated with PD0325901. (G) Volumetric measurements of vehicle-treated or PD0325901-treated Nf1flox/flox;Dhh-Cre mice indicate a decrease in neurofibroma volume treated with 1.5 mg/kg, 5 mg/kg, or 10 mg/kg PD0325901 for 2 months. The y axis shows tumor volume in mm3 quantified by measurements of MRI scans. Each bar represents the difference in tumor volume in an individual animal from day 0 (7 months) to day 60 (9 months). Mixed effects model analysis indicated statistical significance for each dose (P < 0.001; see Supplemental Figure 4).