MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors
Walter J. Jessen, … , Timothy P. Cripe, Nancy Ratner
Walter J. Jessen, … , Timothy P. Cripe, Nancy Ratner
Published December 10, 2012
Citation Information: J Clin Invest. 2013;123(1):340-347. https://doi.org/10.1172/JCI60578.
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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 1

PD0325901 reduces p-ERK and inhibits MPNST cell growth.

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PD0325901 reduces p-ERK and inhibits MPNST cell growth. (A–D) Brown stai...
(A–D) Brown staining indicates detection of p-ERK in paraffin tissue sections. p-ERK is robust in human S462TY MPNST xenografts (A), but is absent 30 minutes after treatment with 10 mg/kg PD0325901 (PD) (B). p-ERK remains detectable at low levels at 6 hours after treatment (C) and returns to pretreatment levels by 24 hours (D). Scale bar: 50 μm. (E) Dose-response analysis of PD0325901 on 5 MPNST cell lines. Effect on cell growth is expressed as percentage of control, and PD0325901 concentration shows nM concentrations on a log scale. (F) Tumor volume (mm3) was significantly reduced in S462TY MPNST xenografts treated with PD0325901 (n = 18) versus control (n = 12). Reduction in tumor volume observed by treatment day 5 was maintained through day 15 (P = 0.004), when many control mice required sacrifice. (E and F) Error bars represent mean ± SEM. (G) Survival of MPNST xenografted mice doubled with 3 months PD0325901 treatment (P < 0.0001).