Samarkina, A. | bioRxiv Science

bioRxiv2022

Androgen Receptor is a Determinant of Melanoma Targeted Drug Resistance

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 pathways involved in BRAFi/MEKi-resistance and poor response to immune checkpoint therapy. We recently showed that androgen receptor (AR) activity is required for melanoma cell proliferation and tumorigenesis. Here we find that AR expression is markedly increased in BRAFi resistant melanoma cells as well as in sensitive cells soon after BRAFi exposure. Increased AR expression is by itself sufficient to render melanoma cells BRAFi-resistant, eliciting transcriptional changes of BRAFi resistant subpopulations and elevated EGFR and SERPINE1 expression of likely clinical significance. Inhibition of AR expression and activity blunts changes in gene expression and suppresses proliferation and tumorigenesis of BRAFi-resistant melanoma cells, enhances MHC I expression and CD8+ T cells infiltration. Our findings point to targeting AR as a possible co-adjuvant approach for the prevention and management of the disease.

cancer biology↗

bioRxiv2020

Sustained Androgen Receptor signaling is a determinant of melanoma cell growth potential and tumorigenesis

Melanoma is a benchmark of major clinical significance for cancer development with greater aggressiveness in the male than the female population. Surprisingly little is known on the role of androgen receptor (AR) signaling in the disease. Irrespectively of expression levels, genetic and pharmacological suppression of AR activity in a large panel of melanoma cells, derived from both male and female patients, suppresses proliferation and self-renewal potential while, conversely, increased AR expression or ligand stimulation enhance proliferation. AR gene silencing in multiple melanoma lines elicits a shared gene expression signature related to interferon- and inflammatory cytokines signaling with an inverse association with DNA repair-associated genes, which is significantly linked with better patients survival. AR plays an essential function in maintenance of genome integrity: in both cultured melanoma cells and tumors, loss of AR activity leads to chromosomal DNA breakage, leakage into the cytoplasm, and stimulator of interferon genes (STING) activation. In vivo, reduced tumorigenesis resulting from AR gene silencing or pharmacological inhibition is associated with intratumor macrophage infiltration and, in an immune competent mouse model, cytotoxic T cell activation. Although at different levels, androgens are produced in both male and female individuals and AR targeting provides an attractive therapy approach for improved management of melanoma irrespective of patients sex and gender. SignificanceThe study uncovers an essential role of androgen receptor (AR) signaling in melanoma cell expansion and tumorigenesis, with loss of AR activity inducing cellular senescence, genomic DNA breakage, a STING dependent inflammatory cascade and immune cells recruitment. Use of AR inhibitors as growth inhibitory and DNA damaging agents in melanoma cells can provide an attractive venue for new combination approaches for management of the disease.

cancer biology↗