Increased CD271 expression by the NF-kB pathway promotes melanoma cell survival and drives acquired resistance to BRAF inhibitor vemurafenib

• Published in: Cell discovery Vol. 1; no. 1; p. 15030
• Main Authors: Lehraiki, Abdelali, Cerezo, Michael, Rouaud, Florian, Abbe, Patricia, Allegra, Marilyne, Kluza, Jerome, Marchetti, Philippe, Imbert, Veronique, Cheli, Yann, Bertolotto, Corine, Ballotti, Robert, Rocchi, Stéphane
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.10.2015; Springer Nature B.V; Nature; Nature Publishing Group
• Subjects: 631/67/1813/1634; 631/80/304; Biomedical and Life Sciences; Cancer; Cell Biology; Cell Culture; Cell Cycle Analysis; Cell Physiology; Life Sciences; Stem Cells; vemurafenib; NF-κB; melanoma; TNFα; CD271; resistance
• ISSN: 2056-5968; 2056-5968
• DOI: 10.1038/celldisc.2015.30

Specific BRAFV600E inhibitors (BRAFi) are highly effective in the treatment of melanoma. However, acquired drug resistances invariably develop after the initial response. Therefore, the identification of new mechanisms of acquired resistance gives important clues towards the development of therapies that could elicit long lasting responses. Here we report that CD271 confers resistance to BRAFi in melanoma cells. The expression of CD271 is increased by BRAFi through a stimulation of tumor necrosis factor-alpha (TNFα) secretion that leads to NF-κB signaling pathway activation. CD271 is upregulated in a subset of BRAFi-resistant melanoma cells. The inhibition of TNFα/NF-κB pathway and CD271 silencing restore the BRAFi sensitivity of resistant melanoma cells. Finally, increase of CD271 expression is validated in BRAFi-resistant xenografts tumors and also in tumors from the patients who relapsed under BRAFi. In summary, these results reveal a novel TNFα/NF-κB/CD271 axis whose activation contributes to the acquisition of resistance to BRAFi and therefore may represent a novel therapeutic target to improve the efficacy of therapy in melanoma.