Androgen receptor (AR) signaling affects response to BRAF / MEK inhibitor therapy in both men and women with melanoma, researchers at the University of Texas MD Anderson Cancer Center showed in a study published today a Nature. The findings provide a new target for combating therapeutic resistance and a possible answer to why men face a worse prognosis than women when diagnosed with melanoma.
RA is a type of nuclear receptor that is activated by the male sex hormone testosterone. Women have lower androgen levels, including testosterone. This research confirms the impact of biological sex on the response to BRAF / MEK-targeted therapy and shows for the first time that these inhibitors increase AR signaling, leading to therapeutic resistance and a poor response to treatment. In preclinical models of melanoma, AR blockade improved the response to BRAF / MEK-targeted therapy in both men and women.
This study, along with other recent publications examining the impact of AR signaling on the response to other types of cancer therapies, such as blocking the immune checkpoint, has enormous implications for the field. We know that men and women suffer from cancer at different rates and have different mortality. Our research raises the possibility that RA and testosterone may be at stake and offer a new goal to improve the response to treatment in both sexes. “
Jennifer Wargo, MD, Senior Corresponding Author, Professor of Genomic Medicine and Surgical Oncology
Biological sex is important for the response to targeted therapy in melanoma
The study began with an observation of a neoadjuvant clinical trial of BRAF / MEK inhibitors in stage III melanoma (NCT02231775) where women had a higher rate of major pathological response (MPR, defined as <10 % of viable tumor at the time of surgery) and non-recurrence survival rates (RFS) than male patients.
To validate these findings, the group studied additional patients with locally advanced metastatic melanoma, including 51 patients treated with neoadjuvant BRAF / MEK inhibitors (30 women and 21 men). The MPR rate was 66% for women and 14% for men, and the two-year RFS rate was 64% for women and 32% for men.
After ruling out other possible factors contributing to MPR -; including age, performance status, body mass index (BMI), disease stage, and mutation status -; the research team validated sexual dimorphism in several other cohorts. The analysis included a total of 664 patients who received BRAF and / or MEK-targeted therapy for stage III or IV melanoma. In several studies, researchers found a trend toward improved progression-free survival (PFS) and overall survival (OS) in women versus men.
Longitudinal evaluation of available tissue samples revealed significantly higher levels of RA in male patients during treatment compared to baseline, and significantly higher levels of RA during treatment in male and female patients on cancer of which did not respond to the combination of targeted therapy.
The role of validated AR signaling in preclinical studies
In collaboration with MD Anderson’s TRACTION (Translational Research to Advance Therapeutics and Innovation in Oncology) platform, the researchers validated their observational findings in several preclinical models.
“This study demonstrates our commitment to transforming patient care through a reverse translation strategy exemplified by MD Anderson,” said co-author Timothy Heffernan, Ph.D., vice president of cancer research. of the Therapeutic Discovery Division and head of MD Anderson. of TRACTION.
First, they showed that female mice implanted with melanoma tumors respond better than male mice to BRAF / MEK inhibitor therapy. When all mice were given testosterone, tumor progression and resistance to treatment in both sexes occurred. Finally, when mice received an RA inhibitor plus targeted therapy, responses to melanoma treatment improved in both sexes.
“Using translational studies in patient samples along with preclinical models, we demonstrated that treatment with BRAF / MEK inhibitors is associated with the regulation of RA in tumor cells, thus promoting resistance. in therapy, “said co-author Joseph Marszalek, Ph.D. ., co-leader of TRACTION. “We found that blocking AR really improved the response to treatment in both men and women, and that activating AR signaling with testosterone abrogated the therapeutic response.”
Recent research has shown that AR-mediated resistance can have an impact on other cancers and types of treatment. Current findings emphasize the need to better understand the impact of receiving hormone therapy while undergoing therapy with BRAF and / or MEK inhibitors for melanoma and other cancers.
“There are many factors that can influence the differences between biological sex and cancer outcomes, but hormones will be one of the next major areas of research,” Wargo said. “The good news is that we already have ways to modulate hormones, so the field is well positioned to develop studies and new therapies to bring to the clinic. There are brilliant researchers at MD Anderson and around the world who are already studying the “use of RA blockade in combination with other cancer treatments in various types of cancer”.
The study was supported by Moon Shot® Melanoma, part of MD Anderson’s Moon Shots® program, a collaborative effort designed to accelerate the development of scientific breakthroughs in clinical advances that save patients’ lives. Texas Cancer Research and Research Institute (RP170002).
Wargo has been a member of the advisory and consulting board of GlaxoSmithKline and Novartis and receives research support.
MD Anderson Cancer Center, University of Texas
Vellano, CP, et al. (2022) Androgen receptor blockade promotes response to BRAF / MEK-targeted therapy. Nature. doi.org/10.1038/s41586-022-04833-8.