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Ref Type Journal Article
PMID (37838724)
Authors Samarkina A, Youssef MK, Ostano P, Ghosh S, Ma M, Tassone B, Proust T, Chiorino G, Levesque MP, Goruppi S, Dotto GP
Title Androgen receptor is a determinant of melanoma targeted drug resistance.
Journal Vol Issue Date Pages Journal Short Title
Nature communications 14 1 2023 Oct 14 6498 Nat Commun
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E melanoma sensitive ARCC4 + Dabrafenib Preclinical - Cell culture Actionable In a preclinical study, the addition of ARCC4 to Tafinlar (dabrafenib) treatment inhibited colony formation in melanoma cell lines harboring BRAF V600E in culture (PMID: 37838724). 37838724
BRAF V600E melanoma sensitive AZD3514 + Dabrafenib Preclinical - Cell culture Actionable In a preclinical study, the addition of AZD3514 to Tafinlar (dabrafenib) treatment inhibited colony formation in melanoma cell lines harboring BRAF V600E in culture (PMID: 37838724). 37838724