Trametinib as a promising therapeutic option in alleviating vascular defects in an endothelial KRAS-induced mouse model

Hum Mol Genet. 2023 Jan 6;32(2):276-289. doi: 10.1093/hmg/ddac169.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Endothelial Cells / pathology
  • Mice
  • Mutation
  • Pancreatic Neoplasms* / genetics
  • Proto-Oncogene Proteins p21(ras)* / genetics

Substances

  • Proto-Oncogene Proteins p21(ras)
  • trametinib