Androgen receptor is a determinant of melanoma targeted drug resistance

Anastasia Samarkina, Markus Kirolos Youssef, Paola Ostano, Soumitra Ghosh, Min Ma, Beatrice Tassone, Tatiana Proust, Giovanna Chiorino, Mitchell P. Levesque, Sandro Goruppi and Gian Paolo Dotto ()
Additional contact information
Anastasia Samarkina: University of Lausanne
Markus Kirolos Youssef: University of Lausanne
Paola Ostano: Edo and Elvo Tempia Valenta Foundation
Soumitra Ghosh: Centre Hospitalier Universitaire Vaudois
Min Ma: University of Lausanne
Beatrice Tassone: University of Lausanne
Tatiana Proust: University of Lausanne
Giovanna Chiorino: Edo and Elvo Tempia Valenta Foundation
Mitchell P. Levesque: University Hospital Zürich, University of Zürich
Sandro Goruppi: Harvard Medical School
Gian Paolo Dotto: University of Lausanne

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Melanoma provides a primary benchmark for targeted drug therapy. Most melanomas with BRAFV600 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 EGFR and SERPINE1 expression, of likely clinical significance. Inhibition of AR expression or activity blunts changes in gene expression and suppresses proliferation and tumorigenesis of BRAFi-resistant melanoma cells, promoting clusters of CD8+ T cells infiltration and cancer cells killing. Our findings point to targeting AR as possible co-therapeutical approach in melanoma treatment.

Date: 2023
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DOI: 10.1038/s41467-023-42239-w

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