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Abstract
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.
Highlights
Melanoma is a major deadly form of skin cancer that arises from the malignant transformation of melanocytes
CD271 is a transmembrane protein that belongs to the tumor necrosis factor receptor superfamily18 and is one of the most widely studied melanoma-initiating cell marker studied so far
We demonstrate that CD271 is differently expressed in melanoma cell lines and cells freshly isolated from patients
Summary
Melanoma is a major deadly form of skin cancer that arises from the malignant transformation of melanocytes. Aberrant expression of splicing isoforms of BRAFV600E [8], or by secondary genetic events, such as overexpression of COT, NRAS mutations or the MEK1C121S mutation [9, 10] has been shown to mediate acquired BRAF inhibitor resistance. Given the diversity and complexity of the identified signaling pathways associated with BRAFi resistance, deciphering the implication of these markers in the mechanisms of resistance and in the underlying melanoma progression is still a priority. This is a prerequisite to develop rational strategies aiming at improving the efficacy of treatment regimens and at reducing the risk of melanoma relapses. We identified CD271 as a new mechanism of acquired resistance of melanoma cells to BRAFi that involves tumor necrosis factor-alpha (TNFα)/NF-κB pathway activation and sustained CD271 expression
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