Faculty, Staff and Student Publications

Publication Date

6-1-2022

Journal

Nature

Abstract

Treatment with BRAF/MEK-targeted therapy has revolutionized care in melanoma and other cancers, however therapeutic resistance is common and innovative treatment strategies are needed1,2. We studied a group of melanoma patients treated with neoadjuvant BRAF/MEK-targeted therapy (NCT02231775, n=51), and observed significantly higher rates of major pathologic response (MPR= <10% viable tumor at resection) and improved recurrence-free survival (RFS) in females versus males (MPR-66% versus 14%, p=0.001; RFS-64% versus 32% at 2 years, p=0.021). Findings were validated in a several additional cohorts2–4 patients with unresectable metastatic melanoma treated with BRAF and/or MEK-targeted therapy (n=664 patients in total), demonstrating improved progression-free survival (PFS) and overall survival (OS) in females versus males in several of these studies. Studies in pre-clinical models demonstrated significantly impaired anti-tumor activity in male versus female BRAF/MEK-treated mice (p=0.006), with significantly higher expression of androgen receptor (AR) in tumors of male and female BRAF/MEK-treated mice versus control (p=0.0006 and 0.0025). Pharmacologic inhibition of AR signaling improved responses to BRAF/MEK-targeted therapy in male and female mice (p=0.018 and p=0.003), whereas induction of AR signaling (via testosterone administration) was associated with significantly impaired response to BRAF/MEK-targeted therapy in males and females (p=0.021 and p<0.0001). Together, these results have important implications for therapy.

Keywords

Androgen Receptor Antagonists, Animals, Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Male, Melanoma, Mice, Mitogen-Activated Protein Kinase Kinases, Molecular Targeted Therapy, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Receptors, Androgen, Skin Neoplasms, Survival Analysis, cancer, targeted therapy, androgen, BRAF

DOI

10.1038/s41586-022-04833-8

PMID

35705814

PMCID

PMC10071594

PubMedCentral® Posted Date

6-15-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

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