The dual role of androgen receptor in melanoma and cancer-associated fibroblasts

There are significant differences in melanoma incidence, mortality, and response to therapy between males and females across all age groups. Males have a worse prognosis and lower survival rates. In addition to behavioral and environmental factors, sex hormone pathways, such as the androgen signaling pathway, may play a role in determining cancer susceptibility, affecting both the cancer and its stromal component. Around 50% of cutaneous melanoma patients have BRAF activating mutations, with over 90% of these being BRAF V600. This mutation causes the kinase in the MAPK pathway to be constitutively activated, leading to uncontrolled proliferation. Targeted BRAF therapies have been developed due to this common mutational background. However, only a minority of treated patients show durable responses, while the remaining patients develop resistance. To address these issues, considerable effort has been devoted to the identification of the primary transcriptional drivers of drug resistance, which can be targeted to improve current therapeutic approaches. This study had two goals: First, to analyze the importance of androgen receptor signaling in the development of the resistance phenotype in melanoma cells, and second, to understand the importance of androgen receptor loss in the surrounding stromal fibroblasts and its impact on the response of melanoma cells to targeted therapy. In summary, our research has shown that long-term application of dabrafenib (BRAFi) to BRAV600E melanoma cells induces androgen receptors, leading to the development of a resistant phenotype. Furthermore, we have demonstrated that the downregulation of AR in stromal fibroblasts results in the upregulation of TDO2, a rate-limiting enzyme in the tryptophan degradation pathway, leading to kynurenine production. Finally, combining dabrafenib and kynurenine treatment resulted in a slight improvement in melanoma cell proliferation assays, suggesting a potential importance of this metabolite during the early phases of drug treatment.