AXL/AKT axis mediated-resistance to BRAF inhibitor depends on PTEN status in melanoma

Related Experiment Video

Updated: Feb 13, 2026

Analysis of Lymph Node Volume by Ultra-High-Frequency Ultrasound Imaging in the Braf/Pten Genetically Engineered Mouse Model of Melanoma
08:18

Analysis of Lymph Node Volume by Ultra-High-Frequency Ultrasound Imaging in the Braf/Pten Genetically Engineered Mouse Model of Melanoma

Published on: September 8, 2021

3.4K

Qiang Zuo1,2, Jing Liu2, Liping Huang1,2

  • 1Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institutes, National Institutes of Health, Bethesda, MD, 20892-4264, USA.

Oncogene
|March 20, 2018
PubMed

Insights

PTEN status dictates resistance to BRAF inhibitors (BRAFi) in melanoma. Blocking the AXL/AKT pathway can restore BRAFi sensitivity in wildtype PTEN melanoma, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Melanoma harbors genetic mutations influencing targeted therapy response and resistance.
  • PTEN inactivation, common in melanoma, impacts drug resistance.
  • BRAF inhibitors (BRAFi) are a key melanoma therapy, but resistance develops.

Purpose of the Study:

  • To investigate the role of PTEN status in mediating resistance to BRAF inhibitors (BRAFi) in melanoma.
  • To identify molecular mechanisms driving BRAFi resistance based on PTEN status.
  • To explore AXL as a therapeutic target for overcoming BRAFi resistance.

Main Methods:

  • Analysis of melanoma cell lines with varying PTEN status.
  • Investigating the roles of AXL, AKT, and ERK pathways in BRAFi resistance.
  • Utilizing shRNA and small molecule inhibitors to block AXL.
  • In vitro and in vivo experiments to assess therapeutic efficacy.

Main Results:

  • AXL/AKT axis-mediated resistance to BRAFi is dependent on PTEN status.
  • Melanoma with wildtype PTEN exhibits resistance via both ERK and AKT pathways, with AXL being a key effector of AKT-driven resistance.
  • PTEN-impaired melanoma cells primarily rely on ERK for resistance.
  • Blocking AXL restores BRAFi sensitivity and inhibits tumor growth in wildtype PTEN melanoma.

Conclusions:

  • PTEN status is a critical determinant of acquired resistance mechanisms to BRAFi in melanoma.
  • The AXL/AKT pathway is a significant contributor to BRAFi resistance in PTEN wildtype melanoma.
  • Targeting AXL presents a promising therapeutic strategy for BRAF-mutant melanoma patients with wildtype PTEN who relapse on BRAFi therapy.

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