Novel treatment strategy for NRAS-mutated melanoma through a selective inhibitor of CD147/VEGFR-2 interaction

Abstract

More than 70% of human NRAS^mut 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 NRAS^mut melanoma cells. It significantly inhibited the malignant properties of NRAS^mut melanomas ex vivo and in vivo. Importantly, NRAS^mut 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 NRAS^mut melanoma when combined with MEKi.