ArticleDrug metabolism and disposition: the biological fate of chemicals2014
Factors influencing the CNS distribution of a novel MEK-1/2 inhibitor: implications for combination therapy for melanoma brain metastases.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
66 citing papers in PubMed, 104 citations in OpenAlex.
- E6201, an intravenous MEK1 inhibitor, achieves an exceptional response in BRAF V600E-mutated metastatic malignant melanoma with brain metastases.Investigational new drugs · 2019Trial
- Window of opportunity study measuring defactinib and avutometinib delivery in glioblastomas.Cancer chemotherapy and pharmacology · 2026Article
- Review
- Targeting Radiation-Induced Glioma-Initiating Cells in Patient-Derived Glioblastoma.bioRxiv : the preprint server for biology · 2025Article
- A spatial map of MAPK-activated immunosuppressive myeloid populations in pediatric low-grade glioma.Nature immunology · 2025Article
- MEK Inhibition in Glioblastoma: Current Perspectives and Future Directions.International journal of molecular sciences · 2025Review
- Drug Combinations Targeting FAK and MEK Overcomes Tumor Heterogeneity in Glioblastoma.Pharmaceutics · 2025Article
- The clinically relevant MEK inhibitor mirdametinib combined with D-cycloserine and prediction error disrupts fear memory in PTSD models.Translational psychiatry · 2024Article
- Leptomeningeal disease in melanoma: An update on the developments in pathophysiology and clinical care.Pigment cell & melanoma research · 2024Review
- A phase I trial of the pan-ERBB inhibitor neratinib combined with the MEK inhibitor trametinib in patients with advanced cancer with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation or KRAS mutation.Cancer chemotherapy and pharmacology · 2023Article
- Kinase-Modulated Bioluminescent Indicators Enable Noninvasive Imaging of Drug Activity in the Brain.ACS central science · 2023Article
- ERBB and P-glycoprotein inhibitors break resistance in relapsed neuroblastoma models through P-glycoprotein.Molecular oncology · 2023Article
- BRAF-mediated brain tumors in adults and children: A review and the Australian and New Zealand experience.Frontiers in oncology · 2023Review
- The MEK Inhibitor Trametinib Improves Outcomes following Subarachnoid Haemorrhage in Female Rats.Pharmaceuticals (Basel, Switzerland) · 2022Article
- MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus.Neuro-oncology · 2022Review
- New Directions in the Therapy of Glioblastoma.Cancers · 2022Review
- Leptomeningeal Metastases: New Opportunities in the Modern Era.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2022Review
- Monitoring of Dabrafenib and Trametinib in Serum and Self-Sampled Capillary Blood in Patients with BRAFV600-Mutant Melanoma.Cancers · 2022Article
- Mechanical Properties of the Extracellular Environment of Human Brain Cells Drive the Effectiveness of Drugs in Fighting Central Nervous System Cancers.Brain sciences · 2022Review
- Target-Agnostic P-Glycoprotein Assessment Yields Strategies to Evade Efflux, Leading to a BRAF Inhibitor with Intracranial Efficacy.Journal of the American Chemical Society · 2022Article
6 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Brain metastases are a major cause of mortality in patients with advanced melanoma. Adequate brain distribution of targeted agents for melanoma will be critical for treatment success. Recently, improvement in overall survival led to US Food and Drug Administration (FDA) approval of the v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors, vemurafenib and dabrafenib, and the mitogen-activated protein kinase kinase-1 (MEK)-1/2 inhibitor, trametinib. However, brain metastases and emergence of resistance remain a significant problem. MEK-1/2 is downstream of BRAF in the mitogen-activated protein kinase (MAPK) signaling pathway, making it an attractive target to combat resistance. The recently approved combination of dabrafenib and trametinib has shown improvement in progression-free survival; however, adequate brain distribution of both compounds is required to effectively treat brain metastases. In previous studies, we found limited brain distribution of dabrafenib. The purpose of the current study was to investigate factors influencing the brain distribution of trametinib. In vitro studies indicated that trametinib is a substrate for both P-glycoprotein (P-gp) and Bcrp, efflux transporters found at the blood-brain barrier. In vivo studies in transgenic mouse models confirmed that P-gp plays an important role in restricting brain distribution of trametinib. The brain-to-plasma partition coefficient (AUCbrain/AUCplasma) was approximately 5-fold higher in Mdr1a/b((-/-)) (P-gp knockout) and Mdr1a/b((-/-))Bcrp1((-/-)) (triple knockout) mice when compared with wild-type and Bcrp1((-/-)) (Bcrp knockout) mice. The brain distribution of trametinib was similar between the wild-type and Bcrp knockout mice. These results show that P-gp plays an important role in limiting brain distribution of trametinib and may have important implications for use of trametinib as single agent or in combination therapy for treatment of melanoma brain metastases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.