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 Helmink, Michael 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, XiaoYan 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 () and Jennifer A. Wargo ()
Additional contact information
Christopher P. Vellano: The University of Texas MD Anderson Cancer Center
Michael G. White: The University of Texas MD Anderson Cancer Center
Miles C. Andrews: The University of Texas MD Anderson Cancer Center
Manoj Chelvanambi: The University of Texas MD Anderson Cancer Center
Russell G. Witt: The University of Texas MD Anderson Cancer Center
Joseph R. Daniele: The University of Texas MD Anderson Cancer Center
Mark Titus: The University of Texas MD Anderson Cancer Center
Jennifer L. McQuade: The University of Texas MD Anderson Cancer Center
Fabio Conforti: European Institute of Oncology, IRCCS
Elizabeth M. Burton: The University of Texas MD Anderson Cancer Center
Matthew J. Lastrapes: The University of Texas MD Anderson Cancer Center
Gabriel Ologun: The University of Texas MD Anderson Cancer Center
Alexandria P. Cogdill: The University of Texas MD Anderson Cancer Center
Golnaz Morad: The University of Texas MD Anderson Cancer Center
Peter Prieto: The University of Texas MD Anderson Cancer Center
Alexander J. Lazar: The University of Texas MD Anderson Cancer Center
Yanshuo Chu: The University of Texas MD Anderson Cancer Center
Guangchun Han: The University of Texas MD Anderson Cancer Center
M. A. Wadud Khan: The University of Texas MD Anderson Cancer Center
Beth Helmink: The University of Texas MD Anderson Cancer Center
Michael A. Davies: The University of Texas MD Anderson Cancer Center
Rodabe N. Amaria: The University of Texas MD Anderson Cancer Center
Jeffrey J. Kovacs: The University of Texas MD Anderson Cancer Center
Scott E. Woodman: The University of Texas MD Anderson Cancer Center
Sapna Patel: The University of Texas MD Anderson Cancer Center
Patrick Hwu: The University of Texas MD Anderson Cancer Center
Michael Peoples: The University of Texas MD Anderson Cancer Center
Jeffrey E. Lee: The University of Texas MD Anderson Cancer Center
Zachary A. Cooper: The University of Texas MD Anderson Cancer Center
Haifeng Zhu: The University of Texas MD Anderson Cancer Center
Guang Gao: The University of Texas MD Anderson Cancer Center
Hiya Banerjee: Novartis Pharmaceuticals
Mike Lau: Novartis Pharma
Jeffrey E. Gershenwald: The University of Texas MD Anderson Cancer Center
Anthony Lucci: The University of Texas MD Anderson Cancer Center
Emily Z. Keung: The University of Texas MD Anderson Cancer Center
Merrick I. Ross: The University of Texas MD Anderson Cancer Center
Laura Pala: European Institute of Oncology, IRCCS
Eleonora Pagan: University of Milan-Bicocca
Rossana Lazcano Segura: The University of Texas MD Anderson Cancer Center
Qian Liu: H. Lee Moffitt Cancer Center and Research Institute
Mikayla S. Borthwick: University of Texas MD Anderson Cancer Center
Eric Lau: H. Lee Moffitt Cancer Center and Research Institute
Melinda S. Yates: University of Texas MD Anderson Cancer Center
Shannon N. Westin: University of Texas MD Anderson Cancer Center
Khalida Wani: The University of Texas MD Anderson Cancer Center
Michael T. Tetzlaff: The University of Texas MD Anderson Cancer Center
Lauren E. Haydu: The University of Texas MD Anderson Cancer Center
Mikhila Mahendra: The University of Texas MD Anderson Cancer Center
XiaoYan Ma: The University of Texas MD Anderson Cancer Center
Christopher Logothetis: The University of Texas MD Anderson Cancer Center
Zachary Kulstad: The University of Texas MD Anderson Cancer Center
Sarah Johnson: The University of Texas MD Anderson Cancer Center
Courtney W. Hudgens: The University of Texas MD Anderson Cancer Center
Ningping Feng: The University of Texas MD Anderson Cancer Center
Lorenzo Federico: The University of Texas MD Anderson Cancer Center
Georgina V. Long: The University of Sydney, and Royal North Shore and Mater Hospitals
P. Andrew Futreal: The University of Texas MD Anderson Cancer Center
Swathi Arur: The University of Texas MD Anderson Cancer Center
Hussein A. Tawbi: The University of Texas MD Anderson Cancer Center
Amy E. Moran: Oregon Health & Science University
Linghua Wang: The University of Texas MD Anderson Cancer Center
Timothy P. Heffernan: The University of Texas MD Anderson Cancer Center
Joseph R. Marszalek: The University of Texas MD Anderson Cancer Center
Jennifer A. Wargo: The University of Texas MD Anderson Cancer Center

Nature, 2022, vol. 606, issue 7915, 797-803

Abstract: 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

Date: 2022
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DOI: 10.1038/s41586-022-04833-8

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