Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy

• Published in: Nature (London) Vol. 606; no. 7915; pp. 797 - 803
• Main Authors: Vellano, Christopher P., White, Michael G., Andrews, Miles C., Chelvanambi, Manoj, Witt, Russell G., Daniele, Joseph R., Titus, Mark, McQuade, Jennifer L., Conforti, Fabio, Burton, Elizabeth M., Lastrapes, Matthew J., Ologun, Gabriel, Cogdill, Alexandria P., Morad, Golnaz, Prieto, Peter, Lazar, Alexander J., Chu, Yanshuo, Han, Guangchun, Khan, M. A. Wadud, Helmink, Beth, Davies, Michael A., Amaria, Rodabe N., Kovacs, Jeffrey J., Woodman, Scott E., Patel, Sapna, Hwu, Patrick, Peoples, Michael, Lee, Jeffrey E., Cooper, Zachary A., Zhu, Haifeng, Gao, Guang, Banerjee, Hiya, Lau, Mike, Gershenwald, Jeffrey E., Lucci, Anthony, Keung, Emily Z., Ross, Merrick I., Pala, Laura, Pagan, Eleonora, Segura, Rossana Lazcano, Liu, Qian, Borthwick, Mikayla S., Lau, Eric, Yates, Melinda S., Westin, Shannon N., Wani, Khalida, Tetzlaff, Michael T., Haydu, Lauren E., Mahendra, Mikhila, Ma, XiaoYan, Logothetis, Christopher, Kulstad, Zachary, Johnson, Sarah, Hudgens, Courtney W., Feng, Ningping, Federico, Lorenzo, Long, Georgina V., Futreal, P. Andrew, Arur, Swathi, Tawbi, Hussein A., Moran, Amy E., Wang, Linghua, Heffernan, Timothy P., Marszalek, Joseph R., Wargo, Jennifer A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.06.2022; Nature Publishing Group
• Subjects: 14/63; 38/91; 42/41; 631/337; 64/60; 692/308/575; Androgen Receptor Antagonists; Androgen receptors; Androgens; Animals; Anticancer properties; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Female; Females; Humanities and Social Sciences; Humans; Male; Males; Melanoma; Melanoma - drug therapy; Melanoma - pathology; Metastases; Metastasis; Mice; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Molecular Targeted Therapy; multidisciplinary; Patients; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Receptors; Receptors, Androgen - metabolism; Response rates; Science; Science (multidisciplinary); Signaling; Skin Neoplasms - drug therapy; Skin Neoplasms - pathology; Survival; Survival Analysis; Testosterone; Therapy; Tumors
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-022-04833-8

Treatment with therapy targeting BRAF and MEK (BRAF/MEK) has revolutionized care in melanoma and other cancers; however, therapeutic resistance is common and innovative treatment strategies are needed 1 , 2 . Here we studied a group of patients with melanoma who were treated with neoadjuvant BRAF/MEK-targeted therapy ( NCT02231775 , n  = 51) and observed significantly higher rates of major pathological response (MPR; ≤10% viable tumour at resection) and improved recurrence-free survival (RFS) in female versus male patients (MPR, 66% versus 14%, P  = 0.001; RFS, 64% versus 32% at 2 years, P  = 0.021). The findings were validated in several additional cohorts 2 – 4 of patients with unresectable metastatic melanoma who were treated with BRAF- and/or MEK-targeted therapy ( n  = 664 patients in total), demonstrating improved progression-free survival and overall survival in female versus male patients in several of these studies. Studies in preclinical models demonstrated significantly impaired anti-tumour activity in male versus female mice after BRAF/MEK-targeted therapy ( P  = 0.006), with significantly higher expression of the androgen receptor in tumours of male and female BRAF/MEK-treated mice versus the control ( P  = 0.0006 and P  = 0.0025). Pharmacological inhibition of androgen receptor signalling improved responses to BRAF/MEK-targeted therapy in male and female mice ( P  = 0.018 and P  = 0.003), whereas induction of androgen receptor signalling (through testosterone administration) was associated with a significantly impaired response to BRAF/MEK-targeted therapy in male and female patients ( P  = 0.021 and P  < 0.0001). Together, these results have important implications for therapy. Treatment with neoadjuvant BRAF/MEK-targeted therapy results in higher rates of major pathological response in female compared with male patients with melanoma, and pharmacological inhibition of androgen receptor signalling improved the responses of male and female mice to BRAF/MEK-targeted therapy.