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

Autor: Landras A; Inserm, UMR_S976, Université de Paris, F-75010, Paris, France., Reger de Moura C; Inserm, UMR_S976, Université de Paris, F-75010, Paris, France.; Pharmacogenomics Department, Hopital Saint Louis, AP-HP, F-75010, Paris, France., Villoutreix BO; Inserm, UMR_S1141, Hopital Robert Debré, F-75019, Paris, France., Battistella M; Inserm, UMR_S976, Université de Paris, F-75010, Paris, France.; Pathology Department, Hopital Saint Louis, AP-HP, F-75010, Paris, France., Sadoux A; Pharmacogenomics Department, Hopital Saint Louis, AP-HP, F-75010, Paris, France., Dumaz N; Inserm, UMR_S976, Université de Paris, F-75010, Paris, France., Menashi S; Pharmacogenomics Department, Hopital Saint Louis, AP-HP, F-75010, Paris, France., Fernández-Recio J; Instituto de Ciencias de la Vid y del Vino (ICVV), CSIC-Universidad de La Rioja-Gobierno de La Rioja, Logroño, Spain., Lebbé C; Inserm, UMR_S976, Université de Paris, F-75010, Paris, France.; Dermatology Department, Hopital Saint Louis, AP-HP, F-75010, Paris, France., Mourah S; Inserm, UMR_S976, Université de Paris, F-75010, Paris, France. samia.mourah@aphp.fr.; Pharmacogenomics Department, Hopital Saint Louis, AP-HP, F-75010, Paris, France. samia.mourah@aphp.fr.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2022 Apr; Vol. 41 (15), pp. 2254-2264. Date of Electronic Publication: 2022 Feb 26.
DOI: 10.1038/s41388-022-02244-7
Abstrakt: 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.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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