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The AhR-SRC axis as a therapeutic vulnerability in BRAFi-resistant melanoma

Anaïs Paris1, Nina Tardif1, Francesca M Baietti2,3

  • 1Univ Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes) - UMR6290, ERL U1305, Rennes, France.

EMBO Molecular Medicine
|October 28, 2022
PubMed

Insights

The Aryl hydrocarbon Receptor (AhR) drives BRAF inhibitor resistance in melanoma by activating the SRC pathway. Targeting this AhR/SRC axis with SRC inhibitors can re-sensitize melanoma cells to BRAFi treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Dermatology

Background:

  • Tumor phenotypic plasticity and drug resistance are critical challenges in melanoma treatment.
  • Nongenetic mechanisms controlling these processes remain poorly understood.

Purpose of the Study:

  • To elucidate the role of the Aryl hydrocarbon Receptor (AhR) in mediating resistance to BRAF inhibitors (BRAFi) in melanoma.
  • To identify therapeutic strategies to overcome BRAFi resistance.

Main Methods:

  • Investigated AhR's role in regulating gene expression programs associated with BRAFi resistance in melanoma cells.
  • Examined the activation of the SRC pathway by AhR.
  • Utilized a preclinical BRAFi-resistant patient-derived xenograft (PDX) melanoma model.
  • Assessed the efficacy of SRC inhibition using dasatinib in combination with BRAFi.

Main Results:

  • AhR directly regulates gene expression programs conferring BRAFi resistance in melanoma.
  • AhR activation promotes an invasive and aggressive resistant phenotype via SRC pathway activation.
  • SRC inhibition with dasatinib re-sensitized melanoma cells to BRAFi in a preclinical model.

Conclusions:

  • The AhR/SRC axis represents a novel therapeutic vulnerability in melanoma.
  • Targeting the AhR/SRC axis offers a clinically compatible approach to reverse BRAFi resistance.
  • Combining SRC inhibitors with BRAFi may delay the development of drug resistance in melanoma.
Keywords:
BRAFi resistancecell plasticityexpressionmelanoma

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