Resistance to BRAF/MEK Inhibition in Melanoma Is Mediated by the Androgen Receptor

BRAF/MEK inhibitors have improved outcomes in melanoma, but resistance is common. The male sex has been associated with worse outcomes in melanoma, and in hormone-responsive cancers, like prostate cancer, the androgen receptor (AR) has been indicated to interact with the MAPK signaling pathway. However, the relationship between AR and BRAF/MEK inhibitor resistance in melanoma has not yet been elucidated. To investigate the role of AR in mediating BRAF/MEK inhibitor resistance in melanoma, Vellano, White, Andrews, Chelvanambi, Witt, and colleagues studied over 600 patients with metastatic melanoma treated with neoadjuvant BRAF/MEK-targeted therapies and showed reduced tumor burden, a higher rate of major pathologic response (MPR), as well as improved relapse-free and progression-free survival in female patients as compared to male patients. Evaluation of AR expression in pretreatment and posttreatment patient samples revealed significantly higher AR expression in male posttreatment samples, while female patients showed a similar trend that did not achieve statistical significance. Moreover, higher AR expression was observed in patients who did not achieve an MPR on BRAF/MEK inhibitors, while those who did showed no significant changes to AR expression. Preclinical models were used to validate these results as well as identify strategies to improve response and survival outcomes and showed that male mice have impaired tumor control as compared to female mice, and pharmacologic inhibition of AR in combination with BRAF/MEK-targeted therapies in mouse models of melanoma demonstrated improved tumor control and reduced tumor size in both male and female mice that could be abrogated by testosterone treatment. Furthermore, AR expression as well as expression of androgen-responsive genes were also found to be higher in mice treated with both testosterone and BRAF/MEK therapies versus BRAF/MEK therapies alone. Overall, these results reveal the role of AR in mediating resistance to BRAF/MEK-targeted therapies in melanoma and suggest that combining AR inhibition with BRAF/MEK inhibitors could lead to improved clinical response.

Vellano CP, White MG, Andrews MC, Chelvanambi M, Witt RG, Daniele JR, et al. Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy. Nature 2022;606:797–803.

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