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Updated: Sep 1, 2025
A Patient-Derived Xenograft Model for Venous Malformation
Published on: June 15, 2020
Trametinib as a promising therapeutic option in alleviating vascular defects in an endothelial KRAS-induced mouse
Ha-Long Nguyen1, Laurence M Boon1,2, Miikka Vikkula1,2
1Human Molecular Genetics, de Duve Institute, University of Louvain, 1200 Brussels, Belgium.
Abstract:
Somatic activating Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations have been reported in patients with arteriovenous malformations. By producing LSL-Kras (G12D); Cdh5 (PAC)-CreERT2 [iEC-Kras (G12D*)] mice, we hoped to activate KRAS within vascular endothelial cells (ECs) to generate an arteriovenous malformation mouse model. Neonatal mice were treated daily with tamoxifen from postnatal (PN) days 1-3. Mortality and phenotypes varied amongst iEC-Kras (G12D*) pups, with only 31.5% surviving at PN14. Phenotypes (focal lesions, vessel dilations) developed in a consistent manner, although with unpredictable severity within multiple soft tissues (such as the brain, liver, heart and brain). Overall, iEC-Kras (G12D*) pups developed significantly larger vascular lumen areas compared with control littermates, beginning at PN8. We subsequently tested whether the MEK inhibitor trametinib could effectively alleviate lesion progression. At PN16, iEC-Kras (G12D*) pup survival improved to 76.9%, and average vessel sizes were closer to controls than in untreated and vehicle-treated mutants. In addition, trametinib treatment helped normalize iEC-Kras (G12D*) vessel morphology in PN14 brains. Thus, trametinib could act as an effective therapy for KRAS-induced vascular malformations in patients.
Insights
Somatic KRAS mutations can cause arteriovenous malformations. A new mouse model showed that the MEK inhibitor trametinib effectively reduced these vascular lesions and improved survival in affected pups.
Area of Science:
- Vascular biology
- Oncology
- Genetics
Background:
- Somatic activating Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations are linked to arteriovenous malformations (AVMs).
- A precise mouse model is needed to study KRAS-driven AVMs in vascular endothelial cells (ECs).
Purpose of the Study:
- To create and characterize a novel mouse model of AVMs by activating KRAS in ECs.
- To evaluate the therapeutic potential of the MEK inhibitor trametinib in this AVM model.
Main Methods:
- Generated LSL-Kras (G12D); Cdh5 (PAC)-CreERT2 [iEC-Kras (G12D*)] mice to activate KRAS in ECs.
- Administered tamoxifen to neonatal mice to induce KRAS activation and observed phenotypes.
- Treated iEC-Kras (G12D*) mice with trametinib and assessed survival, lesion severity, and vascular morphology.
Main Results:
- iEC-Kras (G12D*) mice exhibited increased mortality and developed AVMs with enlarged vascular lumens in multiple tissues.
- Trametinib treatment significantly improved survival rates and reduced vascular lumen size in iEC-Kras (G12D*) mice.
- Trametinib normalized vessel morphology in the brains of treated mice, indicating therapeutic efficacy.
Conclusions:
- The iEC-Kras (G12D*) mouse model recapitulates key features of KRAS-induced AVMs.
- Trametinib demonstrates significant therapeutic potential for treating KRAS-driven vascular malformations.
