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MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus
Peter M K de Blank1, Andrea M Gross2, Srivandana Akshintala2
1Department of Pediatrics, University of Cincinnati and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Abstract:
The wide variety of clinical manifestations of the genetic syndrome neurofibromatosis type 1 (NF1) are driven by overactivation of the RAS pathway. Mitogen-activated protein kinase kinase inhibitors (MEKi) block downstream targets of RAS. The recent regulatory approvals of the MEKi selumetinib for inoperable symptomatic plexiform neurofibromas in children with NF1 have made it the first medical therapy approved for this indication in the United States, the European Union, and elsewhere. Several recently published and ongoing clinical trials have demonstrated that MEKi may have potential benefits for a variety of other NF1 manifestations, and there is broad interest in the field regarding the appropriate clinical use of these agents. In this review, we present the current evidence regarding the use of existing MEKi for a variety of NF1-related manifestations, including tumor (neurofibromas, malignant peripheral nerve sheath tumors, low-grade glioma, and juvenile myelomonocytic leukemia) and non-tumor (bone, pain, and neurocognitive) manifestations. We discuss the potential utility of MEKi in related genetic conditions characterized by overactivation of the RAS pathway (RASopathies). In addition, we review practical treatment considerations for the use of MEKi as well as provide consensus recommendations regarding their clinical use from a panel of experts.
Insights
Mitogen-activated protein kinase kinase inhibitors (MEKi) show promise for treating neurofibromatosis type 1 (NF1) manifestations. This review covers current evidence and expert recommendations for MEKi use in NF1 tumors and non-tumor symptoms.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Neurofibromatosis type 1 (NF1) is a genetic disorder with diverse clinical effects stemming from RAS pathway overactivation.
- Mitogen-activated protein kinase kinase inhibitors (MEKi) target downstream effectors of the RAS pathway.
- Selumetinib, an MEKi, is the first approved medical therapy for inoperable symptomatic plexiform neurofibromas in NF1 patients.
Approach:
- This review synthesizes current evidence on MEKi efficacy for various NF1 manifestations.
- It examines MEKi utility in tumor types (neurofibromas, MPNSTs, gliomas, JMML) and non-tumor symptoms (bone, pain, neurocognition).
- The review also explores MEKi potential in RASopathies and discusses practical treatment considerations and expert consensus recommendations.
Key Points:
- MEKi demonstrate potential benefits across a spectrum of NF1-related conditions.
- Evidence supports MEKi use beyond plexiform neurofibromas, including other tumors and non-tumor symptoms.
- Expert consensus provides guidance on the clinical application of MEKi in NF1 management.
Conclusions:
- MEKi represent a significant therapeutic advance for neurofibromatosis type 1.
- Further research and clinical trials are expanding the role of MEKi in managing NF1 and related RASopathies.
- This review offers a comprehensive overview and practical recommendations for clinicians utilizing MEKi in NF1 care.
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