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Medientyp:
E-Artikel
Titel:
Androgen receptor is a determinant of melanoma targeted drug resistance
Beteiligte:
Samarkina, Anastasia;
Youssef, Markus Kirolos;
Ostano, Paola;
Ghosh, Soumitra;
Ma, Min;
Tassone, Beatrice;
Proust, Tatiana;
Chiorino, Giovanna;
Levesque, Mitchell P.;
Goruppi, Sandro;
Dotto, Gian Paolo
Erschienen:
Springer Science and Business Media LLC, 2023
Erschienen in:Nature Communications
Sprache:
Englisch
DOI:
10.1038/s41467-023-42239-w
ISSN:
2041-1723
Entstehung:
Anmerkungen:
Beschreibung:
<jats:title>Abstract</jats:title><jats:p>Melanoma provides a primary benchmark for targeted drug therapy. Most melanomas with BRAF<jats:sup>V600</jats:sup> mutations regress in response to BRAF/MEK inhibitors (BRAFi/MEKi). However, nearly all relapse within the first two years, and there is a connection between BRAFi/MEKi-resistance and poor response to immune checkpoint therapy. We reported that androgen receptor (AR) activity is required for melanoma cell proliferation and tumorigenesis. We show here that AR expression is markedly increased in BRAFi-resistant melanoma cells, and in sensitive cells soon after BRAFi exposure. Increased AR expression is sufficient to render melanoma cells BRAFi-resistant, eliciting transcriptional changes of BRAFi-resistant subpopulations, including elevated <jats:italic>EGFR</jats:italic> and <jats:italic>SERPINE1</jats:italic> expression, of likely clinical significance. Inhibition of <jats:italic>AR</jats:italic> expression or activity blunts changes in gene expression and suppresses proliferation and tumorigenesis of BRAFi-resistant melanoma cells, promoting clusters of CD8<jats:sup>+</jats:sup> T cells infiltration and cancer cells killing. Our findings point to targeting AR as possible co-therapeutical approach in melanoma treatment.</jats:p>