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 4

Negative feedback regulation of p-ERK in Dhh-Cre neurofibromas.

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Negative feedback regulation of p-ERK in Dhh-Cre neurofibromas. (A–H) ...
(A–H) Brown staining indicates detection of p -ERK in paraffin tissue sections. Nf1fl/fl;Dhh-Cre mouse p-ERK staining is robust in carrier-treated neurofibroma (A and E), but is absent 30 minutes after treatment with 10 mg/kg (B) or 1.5 mg/kg (F) PD0325901. p-ERK becomes detectable 6 hours (C) after treatment with 10 mg/kg PD0325901 and returns to pretreatment levels by 24 hours (D). p-ERK also becomes detectable 6 hours (G) after treatment with 1.5 mg/kg PD0325901, but does not return to pretreatment levels by 24 hours (H). Scale bars: 50 μm. (I–K) qRT-PCR assessment of Ras pathway negative feedback. (I) Independent qRT-PCR confirmation of microarray data (Supplemental Figure 1B) showing overexpression of SPRY4 and DUSP6 in Nf1fl/fl;Dhh-Cre neurofibromas relative to WT mouse nerve. (J) Fold-change in SPRY4 and DUSP6 gene expression relative to pretreatment (control) at 6 and 24 hours after treatment with 10 mg/kg PD0325901, reflecting changes in p-ERK observed in (A–D). (K) Fold change in SPRY4 and DUSP6 gene expression relative to pretreatment (control) at 6 and 24 hours after treatment with 1.5 mg/kg PD0325901, reflecting changes in p-ERK observed in E and F. Error bars represent mean ± SD.