RAS Inhibitor RMC-7977 Blocks Vascular Overgrowth of NRAS^Q61R Mutant Endothelial Cells

Area of Science:

• Molecular Biology and Genetics
• Vascular Biology
• Oncology

Background:

• RAS mutations are implicated in various vascular anomalies, yet effective treatments are scarce.
• Kaposiform lymphangiomatosis (KLA) is a type of vascular anomaly associated with NRAS mutations.
• Targeting aberrant RAS signaling presents a potential therapeutic strategy for these conditions.

Purpose of the Study:

• To evaluate the efficacy of RMC-7977, a multi-selective RAS inhibitor, against NRAS^Q61R mutations.
• To assess the impact of RMC-7977 on endothelial cell (EC) behavior and signaling pathways in vitro and in vivo.
• To determine the therapeutic potential of RMC-7977 for RAS-driven vascular anomalies.

Main Methods:

• Utilized doxycycline-inducible human ECs with wild-type (WT) and NRAS^Q61R mutations.
• Assessed RMC-7977's effects on signaling, proliferation, migration, morphology, and angiopoietin-2 (ANG-2) production in vitro.
• Evaluated RMC-7977 in 3D angiogenesis assays and in vivo mouse xenograft models.

Main Results:

• RMC-7977 dose-dependently inhibited NRAS^Q61R-induced ERK phosphorylation.
• Demonstrated reduced EC proliferation, migration, abnormal morphology, and ANG-2 production.
• Showed decreased vascular area in angiogenesis assays and reduced xenograft weight and vascularity in vivo.

Conclusions:

• RMC-7977 effectively suppresses NRAS^Q61R-mediated signaling and aberrant EC behavior.
• The compound reduced vascular overgrowth in both in vitro and in vivo models.
• RMC-7977 is a promising therapeutic candidate for RAS-driven vascular anomalies, including KLA.