TY - JOUR
T1 - Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy
AU - Vellano, Christopher P.
AU - White, Michael G.
AU - Andrews, Miles C.
AU - Chelvanambi, Manoj
AU - Witt, Russell G.
AU - Daniele, Joseph R.
AU - Titus, Mark
AU - McQuade, Jennifer L.
AU - Conforti, Fabio
AU - Burton, Elizabeth M.
AU - Lastrapes, Matthew J.
AU - Ologun, Gabriel
AU - Cogdill, Alexandria P.
AU - Morad, Golnaz
AU - Prieto, Peter
AU - Lazar, Alexander J.
AU - Chu, Yanshuo
AU - Han, Guangchun
AU - Khan, M. A.Wadud
AU - Helmink, Beth
AU - Davies, Michael A.
AU - Amaria, Rodabe N.
AU - Kovacs, Jeffrey J.
AU - Woodman, Scott E.
AU - Patel, Sapna
AU - Hwu, Patrick
AU - Peoples, Michael
AU - Lee, Jeffrey E.
AU - Cooper, Zachary A.
AU - Zhu, Haifeng
AU - Gao, Guang
AU - Banerjee, Hiya
AU - Lau, Mike
AU - Gershenwald, Jeffrey E.
AU - Lucci, Anthony
AU - Keung, Emily Z.
AU - Ross, Merrick I.
AU - Pala, Laura
AU - Pagan, Eleonora
AU - Segura, Rossana Lazcano
AU - Liu, Qian
AU - Borthwick, Mikayla S.
AU - Lau, Eric
AU - Yates, Melinda S.
AU - Westin, Shannon N.
AU - Wani, Khalida
AU - Tetzlaff, Michael T.
AU - Haydu, Lauren E.
AU - Mahendra, Mikhila
AU - Ma, Xiao Yan
AU - Logothetis, Christopher
AU - Kulstad, Zachary
AU - Johnson, Sarah
AU - Hudgens, Courtney W.
AU - Feng, Ningping
AU - Federico, Lorenzo
AU - Long, Georgina V.
AU - Futreal, P. Andrew
AU - Arur, Swathi
AU - Tawbi, Hussein A.
AU - Moran, Amy E.
AU - Wang, Linghua
AU - Heffernan, Timothy P.
AU - Marszalek, Joseph R.
AU - Wargo, Jennifer A.
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/6/23
Y1 - 2022/6/23
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85131924299&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85131924299&partnerID=8YFLogxK
U2 - 10.1038/s41586-022-04833-8
DO - 10.1038/s41586-022-04833-8
M3 - Article
C2 - 35705814
AN - SCOPUS:85131924299
SN - 0028-0836
VL - 606
SP - 797
EP - 803
JO - Nature
JF - Nature
IS - 7915
ER -