ArticleJCI insight2023
Lymphatic disorders caused by mosaic, activating KRAS variants respond to MEK inhibition.
Article in JCI insight, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 36 citations in OpenAlex.
- From Somatic Driver to Molecular Therapy in Retinal, Choroidal and Periocular Vascular Disease: Mosaicism, Targetable Pathways and Ocular Toxicity.International journal of molecular sciences · 2026Review
- Lymphatic Imaging and Interventions in Children: Current Practice.Cardiovascular and interventional radiology · 2026Review
- The 9th International RASopathies Symposium.American journal of medical genetics. Part A · 2026Article
- RAS-PI3Kα signaling regulates KrasG12D-induced lymphangiogenesis in complex lymphatic anomalies.Disease models & mechanisms · 2026Article
- SHOC2 Is a Novel Cause of Central Conducting Lymphatic Anomaly.American journal of medical genetics. Part A · 2026Article
- Lymphatic Malformations With Activating KRAS Mutations Impair Lymphatic Valve Development Through Matrix Metalloproteinases.Arteriosclerosis, thrombosis, and vascular biology · 2026Article
- Insights into KIF11 pathogenesis in microcephaly-lymphedema-chorioretinopathy syndrome from a lymphatic perspective.JCI insight · 2026Article
- Vascular malformations: from genetics to therapeutics.EMBO molecular medicine · 2026Review
- Further characterisation of immortalised human lymphatic endothelial cells to explore their transcriptomic profile and VEGFC response.Scientific reports · 2025Article
- Molecular targeted treatment in infants with central conducting lymphatic anomalies.European journal of pediatrics · 2025Article
- EBI2-oxysterol signalling regulates VE-cadherin expression and multiple sclerosis CD4Brain, behavior, & immunity - health · 2025Article
- Zebrafish Models of Induced Lymphangiogenesis: Current Advancements and Therapeutic Discovery.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Targeted Therapy for Complex Lymphatic Anomalies in Patients with Noonan Syndrome and Related Disorders.International journal of molecular sciences · 2025Article
- MR Lymphangiography in Pediatrics: Indications, Technique, Findings, and Management.Seminars in interventional radiology · 2025Review
- A single-cell atlas of normal and KRASG12D-malformed lymphatic vessels.JCI insight · 2025Article
- Characteristics and advances in signaling pathways, cellular communication, cell junctions, and oxidative stress in lymphedema.Frontiers in cell and developmental biology · 2025Review
- Targeted medical therapies for vascular anomalies.Hematology. American Society of Hematology. Education Program · 2024Review
- Exploring New Drug Repurposing Opportunities for MEK Inhibitors in RASopathies: A Comprehensive Review of Safety, Efficacy, and Future Perspectives of Trametinib and Selumetinib.Life (Basel, Switzerland) · 2024Review
- Targeted treatment in complex lymphatic anomaly: a case of synergistic efficacy of trametinib and sirolimus.Orphanet journal of rare diseases · 2024Article
- Central conducting lymphatic anomaly: from bench to bedside.The Journal of clinical investigation · 2024Review
Corrections and comments
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Authors and funding
33 authors at 7 institutions in 3 countries.
Funding
Abstract
Central conducting lymphatic anomaly (CCLA) due to congenital maldevelopment of the lymphatics can result in debilitating and life-threatening disease with limited treatment options. We identified 4 individuals with CCLA, lymphedema, and microcystic lymphatic malformation due to pathogenic, mosaic variants in KRAS. To determine the functional impact of these variants and identify a targeted therapy for these individuals, we used primary human dermal lymphatic endothelial cells (HDLECs) and zebrafish larvae to model the lymphatic dysplasia. Expression of the p.Gly12Asp and p.Gly13Asp variants in HDLECs in a 2‑dimensional (2D) model and 3D organoid model led to increased ERK phosphorylation, demonstrating these variants activate the RAS/MAPK pathway. Expression of activating KRAS variants in the venous and lymphatic endothelium in zebrafish resulted in lymphatic dysplasia and edema similar to the individuals in the study. Treatment with MEK inhibition significantly reduced the phenotypes in both the organoid and the zebrafish model systems. In conclusion, we present the molecular characterization of the observed lymphatic anomalies due to pathogenic, somatic, activating KRAS variants in humans. Our preclinical studies suggest that MEK inhibition should be studied in future clinical trials for CCLA due to activating KRAS pathogenic variants.
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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.