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

Christopher P. Vellano, Michael G. White, Miles C. Andrews, Manoj Chelvanambi, Russell G. Witt, Joseph R. Daniele, Mark Titus, Jennifer L. McQuade, Fabio Conforti, Elizabeth M. Burton, Matthew J. Lastrapes, Gabriel Ologun, Alexandria P. Cogdill, Golnaz Morad, Peter Prieto, Alexander J. Lazar, Yanshuo Chu, Guangchun Han, M. A.Wadud Khan, Beth HelminkMichael A. Davies, Rodabe N. Amaria, Jeffrey J. Kovacs, Scott E. Woodman, Sapna Patel, Patrick Hwu, Michael Peoples, Jeffrey E. Lee, Zachary A. Cooper, Haifeng Zhu, Guang Gao, Hiya Banerjee, Mike Lau, Jeffrey E. Gershenwald, Anthony Lucci, Emily Z. Keung, Merrick I. Ross, Laura Pala, Eleonora Pagan, Rossana Lazcano Segura, Qian Liu, Mikayla S. Borthwick, Eric Lau, Melinda S. Yates, Shannon N. Westin, Khalida Wani, Michael T. Tetzlaff, Lauren E. Haydu, Mikhila Mahendra, Xiao Yan Ma, Christopher Logothetis, Zachary Kulstad, Sarah Johnson, Courtney W. Hudgens, Ningping Feng, Lorenzo Federico, Georgina V. Long, P. Andrew Futreal, Swathi Arur, Hussein A. Tawbi, Amy E. Moran, Linghua Wang, Timothy P. Heffernan, Joseph R. Marszalek, Jennifer A. Wargo

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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 needed1,2. 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 cohorts2–4 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.

Original languageEnglish
Pages (from-to)797-803
Number of pages7
JournalNature
Volume606
Issue number7915
DOIs
StatePublished - Jun 23 2022

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