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Updated: Jul 13, 2025

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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Androgen receptor is a determinant of melanoma targeted drug resistance

Anastasia Samarkina1, Markus Kirolos Youssef1, Paola Ostano2

  • 1Department of Immunobiology, University of Lausanne, Épalinges, Switzerland.

Nature Communications
|October 14, 2023
PubMed

Insights

Targeting androgen receptor (AR) can overcome resistance to BRAF/MEK inhibitors (BRAFi/MEKi) in melanoma. Inhibiting AR suppresses tumor growth and enhances anti-cancer immune responses in resistant melanoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Melanoma treatment often involves BRAF/MEK inhibitors (BRAFi/MEKi), but resistance develops rapidly.
  • BRAFi/MEKi resistance is linked to poor outcomes with immune checkpoint therapy.
  • Androgen receptor (AR) activity is crucial for melanoma cell proliferation.

Purpose of the Study:

  • To investigate the role of androgen receptor (AR) in BRAF/MEK inhibitor (BRAFi/MEKi) resistance in melanoma.
  • To determine if AR inhibition can overcome BRAFi/MEKi resistance and improve therapeutic outcomes.

Main Methods:

  • Assessed AR expression in sensitive and resistant melanoma cells.
  • Utilized genetic and pharmacological inhibition of AR.
  • Analyzed transcriptional changes associated with AR activity.
  • Evaluated the impact of AR inhibition on tumor growth and immune cell infiltration in vivo.

Main Results:

  • AR expression is significantly increased in BRAFi-resistant melanoma cells and upon BRAFi exposure in sensitive cells.
  • Elevated AR expression is sufficient to induce BRAFi resistance, altering gene expression profiles (e.g., EGFR, SERPINE1).
  • AR inhibition reversed resistance-associated gene expression, suppressed tumor proliferation, and promoted CD8+ T cell infiltration and cancer cell killing.

Conclusions:

  • Androgen receptor (AR) plays a critical role in the development and maintenance of BRAF/MEK inhibitor (BRAFi/MEKi) resistance in melanoma.
  • Targeting AR represents a promising co-therapeutic strategy to overcome BRAFi/MEKi resistance and enhance anti-tumor immunity in melanoma.

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