Preclinical Assessment of MEK1/2 Inhibitors for Neurofibromatosis Type 2-Associated Schwannomas Reveal Differences in Efficacy and Drug Resistance Development.

Preclinical Assessment of MEK1/2 Inhibitors for Neurofibromatosis Type 2-Associated Schwannomas Reveal Differences in Efficacy and Drug Resistance Development.

Neuro Oncol. 2019 Jan 06;:

Authors: Fuse MA, Dinh CT, Vitte J, Kirkpatrick J, Mindos T, Plati SK, Young JI, Huang J, Carlstedt A, Franco MC, Brnjos K, Nagamoto J, Petrilli A, Copik AJ, Soulakova JN, Bracho O, Yan D, Mittal R, Shen R, Telischi FF, Morrison H, Giovannini M, Liu XZ, Chang LS, Fernandez-Valle C

Abstract
Background: Neurofibromatosis type 2 (NF2) is a genetic tumor-predisposition disorder caused by NF2/merlin tumor suppressor gene inactivation. The hallmark of NF2 is formation of bilateral vestibular schwannomas (VS). Because merlin modulates activity of the Ras/Raf/MEK/ERK pathway, we investigated repurposing drugs targeting MEK1/2 as a treatment for NF2-associated schwannomas.
Methods: Mouse and human merlin-deficient Schwann cell lines (MD-MSC/HSC) were screened against six MEK1/2 inhibitors. Efficacious drugs were tested in orthotopic allograft and NF2 transgenic mouse models. Pathway and proteome analyses were conducted. Drug efficacy was examined in primary human VS cells with NF2 mutations and correlated with DNA methylation patterns.
Results: Trametinib, PD0325901, and cobimetinib were most effective in reducing MD-MSC/HSC viability. Each decreased pERK1/2 and cyclin D1, increased p27, and induced caspase 3 cleavage in MD-MSCs. Proteomic analysis confirmed cell cycle arrest and activation of pro-apoptotic pathways in trametinib-treated MD-MSCs. The three inhibitors slowed allograft growth, however decreased pERK1/2, cyclin D1, and Ki67 levels were observed only in PD0325901 and cobimetinib-treated grafts. Tumor burden and average tumor size was reduced in trametinib-treated NF2 transgenic mice, however tumors did not exhibit reduced pERK1/2 levels. Trametinib and PD0325901 modestly reduced viability of several primary human VS cell cultures with NF2 mutations. DNA methylation analysis of PD0325901 resistant versus susceptible VS identified genes that could contribute to drug-resistance.
Conclusion: MEK inhibitors exhibited differences in anti-tumor efficacy resistance in schwannoma models with possible emergence of trametinib resistance. The results support further investigation of MEK inhibitors in combination with other targeted drugs for NF2 schwannomas.

PMID: 30615146 [PubMed - as supplied by publisher]

from A via a.sfakia on Inoreader http://bit.ly/2SDDoFH