Androgen receptor is a determinant of melanoma targeted drug resistance.

Details

Serval ID
serval:BIB_CD9AA3E3CEE6
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Androgen receptor is a determinant of melanoma targeted drug resistance.
Journal
Nature communications
Author(s)
Samarkina A., Youssef M.K., Ostano P., Ghosh S., Ma M., Tassone B., Proust T., Chiorino G., Levesque M.P., Goruppi S., Dotto G.P.
ISSN
2041-1723 (Electronic)
ISSN-L
2041-1723
Publication state
Published
Issued date
14/10/2023
Peer-reviewed
Oui
Volume
14
Number
1
Pages
6498
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
Melanoma provides a primary benchmark for targeted drug therapy. Most melanomas with BRAF <sup>V600</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 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 <sup>+</sup> T cells infiltration and cancer cells killing. Our findings point to targeting AR as possible co-therapeutical approach in melanoma treatment.
Keywords
Humans, Proto-Oncogene Proteins B-raf/metabolism, CD8-Positive T-Lymphocytes/metabolism, Receptors, Androgen/genetics, Drug Resistance, Neoplasm/genetics, Neoplasm Recurrence, Local/drug therapy, Melanoma/drug therapy, Melanoma/genetics, Melanoma/metabolism, Mitogen-Activated Protein Kinase Kinases, Carcinogenesis, Protein Kinase Inhibitors/pharmacology, Cell Line, Tumor
Pubmed
Web of science
Open Access
Yes
Create date
19/10/2023 15:09
Last modification date
19/12/2023 7:15
Usage data