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Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer

Anna Adam-Artigues1, Enrique J Arenas2,3, Alex Martínez-Sabadell2

  • 1INCLIVA Biomedical Research Institute, Valencia 46010, Spain.

Science Advances
|May 20, 2022
PubMed

Insights

AXL overexpression drives resistance to anti-HER2 therapy in breast cancer. Targeting AXL with trastuzumab offers a promising strategy for improving treatment outcomes in HER2-positive patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Anti-HER2 therapies have significantly improved outcomes for HER2-positive breast cancer.
  • Treatment resistance remains a major challenge, necessitating the identification of resistance mechanisms.

Purpose of the Study:

  • To identify key mechanisms of trastuzumab resistance in HER2-positive breast cancer.
  • To evaluate AXL as a potential therapeutic target and prognostic biomarker.

Main Methods:

  • Investigated AXL overexpression as a mechanism of trastuzumab resistance.
  • Utilized genetic depletion and pharmacological inhibition of AXL in vitro and in vivo.
  • Analyzed AXL expression in patient-derived xenograft models and clinical trial data (PAMELA trial).

Main Results:

  • AXL overexpression was identified as a critical mechanism of trastuzumab resistance.
  • AXL inhibition restored sensitivity to trastuzumab, leading to complete tumor regression in resistant models.
  • AXL expression predicted prognosis in HER2-positive breast cancer and changed during neoadjuvant dual HER2 blockade.

Conclusions:

  • Targeting AXL in combination with anti-HER2 drugs is a promising strategy for HER2-amplified breast cancer with high AXL expression.
  • AXL serves as a potential druggable prognostic biomarker for HER2-positive breast cancer.

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