Androgen Receptor Signaling May Contribute to Melanoma Treatment Resistance

In a study involving 664 patients receiving neoadjuvant BRAF- or MEK-targeted therapy across several cohorts, the researchers observed significantly higher rates of major pathological response (MPR) and improved recurrence-free survival (RFS) in female versus male patients, with MPRs of 66% versus 14%, and RFS at 64% versus 32% at two years, respectively. Tumor samples taken before and during treatment contained higher levels of androgen receptors in male patients during treatment compared with before treatment. Female patients’ androgen receptor levels also increased during treatment, but to a much lower extent.

The researchers duplicated the gender difference in mouse models, then used CRISPR to delete the gene for androgen receptor in melanoma cells before implanting them into male and female mice. They found that without the androgen receptor increase, both male and female mice responded equally to BRAF or MEK inhibitors, even when given testosterone to boost androgen receptor signaling.

“There’s a lot of potential, but a lot more research is needed to better understand the impact of hormone signaling on the response to both targeted therapies and immunotherapy,” the authors said in a subsequent interview (https://www.cancer.gov/news-events/cancer-currents-blog/2022/melanoma-treatment-androgen-receptor). They added that because BRAF and MEK inhibitors are being investigated for use in other cancers such as thyroid and lung, “our studies have to expand beyond melanoma to study the impact of androgen receptor signaling across BRAF-variant tumors.”