AR Signaling Plays a Role in Diminished Response to BRAF/MEK Inhibitors

Major pathological response (MPR) and recurrence-free survival (RFS) rates were improved in women vs men who with melanoma who received BRAF/MEK inhibitor therapy in the neoadjuvant setting, according to a study recently published in Nature.^1,2 Investigators from The University of Texas MD Anderson Cancer Center (MD Anderson) in Houston attributed this difference to the influence of androgen receptor (AR) signaling in tumors.¹

“A number of clinical trials have shown that [men] often have a worse response than [women] to certain cancer therapeutics,” Joseph Marzalek, PhD, a coauthor on the study and the head of translational biology at MD Anderson, said in an email to OncLive®. “We zeroed in on the AR being expressed to a higher level in tumors implanted in male mice, presumably being stabilized by the presence of testosterone, and the induction of expression following treatment with BRAF/MEK inhibitors. Importantly, we also observed this in pre- and on-treatment patient clinical samples from [men], but not [women].” 

Results of several studies highlighted the difference in outcomes when results were stratified by biological sex. For example, Investigators examined a cohort of 51 patients with locoregional, stage IIIB-C melanoma harboring a BRAFV600 mutation who were treated with neoadjuvant BRAF/MEK-targeted therapy in a phase 2 clinical trial (NCT02231775). Investigators observed higher rates of MPR among women (n = 30) compared with men (n = 21) at 66% vs 14%, respectively (P = .001). Additionally, women also exhibited a higher 2-year RFS rate (64%) compared with men (32%; P = .021).²

In an analysis of 211 patients who received dabrafenib (Taflinar) plus trametinib (Mekinist) on the phase 3 COMBI-d trial (NCT01597908), the 2-year relative risk of disease progression was 19% (RR, 0.81; 95% CI, 0.67-0.98; P = .03) for women vs men. The 2-year progression-free survival (PFS) rate for women was 38.0% (95% CI, 28.0%-47.9%) vs 23.2% (95% CI, 15.0%-31.5%) for men. The 4-year PFS rates were 19.0% (95% CI, 10.2%-27.7%) vs 19.2% (95% CI, 11.4%-26.8%), respectively.

In terms of overall survival (OS), the 2-year relative risk was 0.73 (95% CI, 0.54-0.99; P = .04). The 2-, 4-, and 6-year OS rates for women were 59.7%, 39.7%, and 34.5%, respectively, compared with 44.8%, 30.6%, and 26.5%, respectively, for men.²

Investigators then collaborated with the Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform at MD Anderson to further confirm their findings in multiple preclinical models. Findings from the preclinical studies displayed impaired antitumor activity in male mice following BRAF/MEK targeted therapy compared with their female counterparts (P = .006). Additionally, both the male mice and the female mice had higher ARexpression after treatment with BRAF/MEK inhibitors compared with the control group (P = .0006 and P = .0025, respectively).²

When AR signaling was inhibited with an additional agent, the responses to BRAF/MEK-targeted therapy improved in both male mice and female mice (P = .018 and P = .003, respectively). Conversely, AR signaling induction via testosterone administration diminished the response to BRAF/MEK inhibitors in both male mice and female mice (P = .021 and P < .0001, respectively).²

“To identify the mechanism that led to this dimorphism, TRACTION performed preclinical studies in mouse models of melanoma and observed the same differential response to the BRAF/MEK inhibitor combination, with females responding better than males,” Marzalek said. “To confirm this, we manipulated the signaling pathway by supplementing female mice with testosterone, which led to reduced response and an increase in AR protein expression.” 

Removing AR from tumors via CRISPR knockout abrogated the differential response in males and females, establishing that AR expression in tumors is required for the resistance, Marzalek added. The findings from their study suggest that response to BRAF/MEK inhibitor combination therapy is abrogated by testosterone, driving AR signaling to promote tumor-cell survival and that blocking AR signaling with currently available therapeutics could lead to deeper and more durable responses, Marzalek said.

“This is an excellent example of team science that was fostered by MD Anderson’s Moon Shots program, where our preclinical TRACTION partners with MD Anderson’s clinical teams to model and define the mechanisms driving clinical observations, and advance them into actionable therapeutic opportunities,” Marzalek said. “The next step will be to evaluate the potential benefit of BRAF/MEK inhibitor combination therapy in the clinic in melanoma, and potentially other indications where differential responses are observed and/or AR signaling is active. In addition, it will be worthwhile to explore whether AR signaling plays a role in promoting resistance to other therapies.” 

References

1. Androgen receptor signaling contributes to targeted therapy resistance in melanoma. News release. The University of Texas MD Anderson Cancer Center. June 15, 2022. Accessed July 6, 2022. bit.ly/3OQi259
2. Vellano CP, White MG, Wargo JA, et al. Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy. Nature. 2022;606(7915):797-803. doi:10.1038/s41586-022-04833-8