ArticleNeuro-oncology2019
Preclinical assessment of MEK1/2 inhibitors for neurofibromatosis type 2-associated schwannomas reveals differences in efficacy and drug resistance development.
Article in Neuro-oncology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
25 citing papers in PubMed, 36 citations in OpenAlex.
- A review of targeted therapies for NF2-related vestibular schwannoma: molecular pathogenesis, emerging therapeutics, and future clinical horizons.Journal of neuro-oncology · 2026Review
- Vestibular schwannoma: genetic and epigenetic mechanisms, hearing loss, and emerging therapies.Journal of neuro-oncology · 2026Review
- Article
- BET proteins mediate survival mechanisms in human schwannoma model cells challenged with trametinib but not brigatinib.Oncogene · 2025Article
- NF2-associated schwannomatosis (NF2): genetics, manifestations, and emerging therapeutic approaches.Trends in molecular medicine · 2025Article
- Capacity for Compensatory Cyclin D2 Response Confers Trametinib Resistance in Canine Mucosal Melanoma.Cancers · 2025Article
- Therapeutic effect of novel drug candidate, PRG-N-01, on NF2 syndrome-related tumor.Neuro-oncology · 2025Article
- Capacity for compensatory cyclin D2 response confers trametinib resistance in canine mucosal melanoma.bioRxiv : the preprint server for biology · 2025Article
- Current molecular understanding of central nervous system schwannomas.Acta neuropathologica communications · 2025Review
- Single-cell multi-omic analysis of the vestibular schwannoma ecosystem uncovers a nerve injury-like state.Nature communications · 2024Article
- Cotargeting Phosphoinositide 3-Kinase and Focal Adhesion Kinase Pathways Inhibits Proliferation of NF2 Schwannoma Cells.Molecular cancer therapeutics · 2023Article
- The antiviral effects of a MEK1/2 inhibitor promote tumor regression in a preclinical model of human papillomavirus infection-induced tumorigenesis.Antiviral research · 2023Article
- Comprehensive Genomic Profiling of NF2-Mutated Kidney Tumors Reveals Potential Targets for Therapy.The oncologist · 2023Article
- Concurrent inhibition of FAK/SRC and MEK overcomes MEK inhibitor resistance in Neurofibromatosis Type I related malignant peripheral nerve sheath tumors.Frontiers in oncology · 2022Article
- Preclinical Assessment of MEK Inhibitors for Malignant Peripheral Nerve Sheath Tumors Reveals Differences in Efficacy and Adaptive Response.Frontiers in oncology · 2022Article
- CUDC907, a dual phosphoinositide-3 kinase/histone deacetylase inhibitor, promotes apoptosis of NF2 Schwannoma cells.Oncotarget · 2022Article
- Targeted Therapies for the Neurofibromatoses.Cancers · 2021Review
- Review
- MEK inhibitors - novel targeted therapies of neurofibromatosis associated benign and malignant lesions.Biomarker research · 2021Review
- Neurofibromatosis Type 2 (NF2) and the Implications for Vestibular Schwannoma and Meningioma Pathogenesis.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
25 authors at 6 institutions in 2 countries.
Funding
Abstract
backgroundNeurofibromatosis 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/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, we investigated repurposing drugs targeting MEK1 and/or MEK2 as a treatment for NF2-associated schwannomas.
methodsMouse and human merlin-deficient Schwann cell lines (MD-MSC/HSC) were screened against 6 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.
resultsTrametinib, PD0325901, and cobimetinib were most effective in reducing MD-MSC/HSC viability. Each decreased phosphorylated 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 3 inhibitors slowed allograft growth; however, decreased pERK1/2, cyclin D1, and Ki-67 levels were observed only in PD0325901 and cobimetinib-treated grafts. Tumor burden and average tumor size were 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.
conclusionMEK inhibitors exhibited differences in antitumor 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.
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