학술논문
Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy
Document Type
Article
Author
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.
Source
Nature; 20220101, Issue: Preprints p1-7, 7p
Subject
Language
ISSN
00280836; 14764687
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 cohorts2–4of 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.