Related Experiment Video
Updated: Oct 2, 2025
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
Novel treatment strategy for NRAS-mutated melanoma through a selective inhibitor of CD147/VEGFR-2 interaction
Alexandra Landras1, Coralie Reger de Moura1,2, Bruno O Villoutreix3
1Inserm, UMR_S976, Université de Paris, F-75010, Paris, France.
Abstract:
More than 70% of human NRASmut melanomas are resistant to MEK inhibitors highlighting the crucial need for efficient therapeutic strategies for these tumors. CD147, a membrane receptor, is overexpressed in most cancers including melanoma and is associated with poor prognosis. We show here that CD147i, a specific inhibitor of CD147/VEGFR-2 interaction represents a potential therapeutic strategy for NRASmut melanoma cells. It significantly inhibited the malignant properties of NRASmut melanomas ex vivo and in vivo. Importantly, NRASmut patient's-derived xenografts, which were resistant to MEKi, became sensitive when combined with CD147i leading to decreased proliferation ex vivo and tumor regression in vivo. Mechanistic studies revealed that CD147i effects were mediated through STAT3 pathway. These data bring a proof of concept on the impact of the inhibition of CD147/VEGFR-2 interaction on melanoma progression and represents a new therapeutic opportunity for NRASmut melanoma when combined with MEKi.
Insights
A new drug targeting CD147 (a protein overexpressed in melanoma) shows promise for treating NRAS-mutant melanomas resistant to MEK inhibitors. Combining CD147 inhibition with MEK inhibitors may offer a novel therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Over 70% of NRAS-mutant melanomas exhibit resistance to MEK inhibitors, necessitating alternative treatment strategies.
- CD147, a cell surface receptor, is frequently overexpressed in various cancers, including melanoma, and correlates with poor patient prognosis.
Purpose of the Study:
- To evaluate the therapeutic potential of CD147i, a specific inhibitor of the CD147/VEGFR-2 interaction, against NRAS-mutant melanoma.
- To investigate the efficacy of combining CD147i with MEK inhibitors (MEKi) in preclinical models of NRAS-mutant melanoma.
Main Methods:
- Assessment of CD147i's effect on malignant properties of NRAS-mutant melanoma cells ex vivo and in vivo.
- Evaluation of combination therapy with CD147i and MEKi in patient-derived xenografts (PDXs) resistant to MEKi.
- Mechanistic studies to elucidate the signaling pathways affected by CD147i, focusing on the STAT3 pathway.
Main Results:
- CD147i significantly inhibited the malignant characteristics of NRAS-mutant melanomas in both ex vivo and in vivo settings.
- Combination therapy of CD147i and MEKi resensitized MEKi-resistant NRAS-mutant xenografts, leading to reduced proliferation and tumor regression.
- The therapeutic effects of CD147i were found to be mediated through the modulation of the STAT3 signaling pathway.
Conclusions:
- Inhibition of the CD147/VEGFR-2 interaction represents a viable therapeutic approach for NRAS-mutant melanoma.
- Combining CD147i with MEKi offers a promising new strategy to overcome MEK inhibitor resistance in NRAS-mutant melanoma.
- These findings provide a proof of concept for targeting CD147/VEGFR-2 interaction as a therapeutic opportunity in melanoma.
