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

Nature. 2022 Jun;606(7915):797-803. doi: 10.1038/s41586-022-04833-8. Epub 2022 Jun 15.


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.

MeSH terms

  • Androgen Receptor Antagonists*
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Female
  • Humans
  • Male
  • Melanoma* / drug therapy
  • Melanoma* / pathology
  • Mice
  • Mitogen-Activated Protein Kinase Kinases* / antagonists & inhibitors
  • Molecular Targeted Therapy*
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins B-raf* / antagonists & inhibitors
  • Receptors, Androgen* / metabolism
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / pathology
  • Survival Analysis


  • Androgen Receptor Antagonists
  • Protein Kinase Inhibitors
  • Receptors, Androgen
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Mitogen-Activated Protein Kinase Kinases