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

Author

Listed:
  • 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
    Monash University)

  • 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
    Guthrie Courtland Medical Center)

  • Alexandria P. Cogdill

    (The University of Texas MD Anderson Cancer Center
    Immunai)

  • Golnaz Morad

    (The University of Texas MD Anderson Cancer Center)

  • Peter Prieto

    (The University of Texas MD Anderson Cancer Center
    University of Rochester)

  • Alexander J. Lazar

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center
    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
    Washington University in St Louis)

  • 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
    Moffitt 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
    AstraZeneca)

  • 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
    University of California)

  • 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
    The University of Texas MD Anderson Cancer Center)

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

Suggested Citation

  • 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 & Matth, 2022. "Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy," Nature, Nature, vol. 606(7915), pages 797-803, June.
    • Handle: RePEc:nat:nature:v:606:y:2022:i:7915:d:10.1038_s41586-022-04833-8
    DOI: 10.1038/s41586-022-04833-8
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    Citations

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    Cited by:

    1. Luye An & Dahihm Kim & Leanne R. Donahue & Menansili Abraham Mejooli & Chi-Yong Eom & Nozomi Nishimura & Andrew C. White, 2024. "Sexual dimorphism in melanocyte stem cell behavior reveals combinational therapeutic strategies for cutaneous repigmentation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Anastasia Samarkina & Markus Kirolos Youssef & Paola Ostano & Soumitra Ghosh & Min Ma & Beatrice Tassone & Tatiana Proust & Giovanna Chiorino & Mitchell P. Levesque & Sandro Goruppi & Gian Paolo Dotto, 2023. "Androgen receptor is a determinant of melanoma targeted drug resistance," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Qian Liu & Emma Adhikari & Daniel K. Lester & Bin Fang & Joseph O. Johnson & Yijun Tian & Andrea T. Mockabee-Macias & Victoria Izumi & Kelly M. Guzman & Michael G. White & John M. Koomen & Jennifer A., 2024. "Androgen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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