Authors
Sara Alharbi, Svatava Merkle, Patricia Pastura, C Griffin McDaniel, George S Zaky, Andrew M Waters, Timothy D Le Cras
Published in
Journal of cellular and molecular medicine. Volume 30. Issue 15. Pages e71316.
Abstract
RAS mutations occur in patients with several types of vascular anomalies, but effective treatments remain limited. To address this need, we evaluated the RAS (ON) multi-selective inhibitor RMC-7977 in human endothelial cells (ECs) expressing the NRASQ61R mutation found in kaposiform lymphangiomatosis (KLA). RMC-7977 was evaluated using in vitro and in vivo models. Doxycycline-inducible NRASWT and NRASQ61R human ECs were treated with RMC-7977 (3.12-100 nM) or vehicle. We assessed signalling pathways, proliferation, migration, morphology, and angiopoietin-2 (ANG-2) production. NRASQ61R ECs in a 3D angiogenesis assay were also treated with RMC-7977. For in vivo studies, NRASQ61R ECs were injected into flanks of nude mice on a doxycycline diet to generate xenografts. Mice received oral RMC-7977 or vehicle, and xenografts were collected after 11 days. RMC-7977 inhibited NRASQ61R-induced ERK phosphorylation and reduced proliferation, migration, spindle-like morphology, and ANG-2 production in a dose-dependent manner. RMC-7977 reduced vascular area in the angiogenesis assay. In vivo, RMC-7977 reduced xenograft weight, vascular area, and p-ERK staining. Overall, RMC-7977 suppressed NRASQ61R-mediated signalling, aberrant EC behaviour, and ANG-2 production in vitro and reduced vascular overgrowth in angiogenesis assays and mouse xenografts. Therefore, RMC-7977 may be a promising therapeutic candidate for RAS-driven vascular anomalies, including KLA.
PMID:
42576614
Bibliographic data and abstract were imported from PubMed on 11 Aug 2026.
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