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AXL - a new player in resistance to HER2 blockade

Anna Adam-Artigues1, Enrique J Arenas2, Joaquín Arribas3

  • 1INCLIVA Biomedical Research Institute, Spain.

Cancer Treatment Reviews
|October 21, 2023
PubMed

Insights

HER2-positive cancers can develop resistance to anti-HER2 therapies. Targeting AXL, a receptor tyrosine kinase, alongside HER2 shows promise in overcoming this resistance and improving patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • HER2 (Human Epidermal growth factor Receptor 2) is a key driver in several solid tumors, including breast, esophageal, and gastric cancers.
  • HER2 overexpression is linked to aggressive disease and poor prognosis, with targeted anti-HER2 therapies being the standard of care.
  • Therapeutic resistance to anti-HER2 agents is a significant clinical challenge, necessitating novel treatment strategies.

Purpose of the Study:

  • To investigate the role of AXL, a receptor tyrosine kinase, in mediating resistance to anti-HER2 therapies.
  • To explore the potential of co-targeting AXL and HER2 as a strategy to overcome therapeutic resistance.
  • To evaluate AXL as a prognostic and predictive biomarker in HER2-positive cancers.

Main Methods:

  • Review of preclinical studies investigating the mechanisms of anti-HER2 resistance.
  • Analysis of AXL signaling pathways and their crosstalk with HER2.
  • Evaluation of in vitro and in vivo models of AXL inhibition in overcoming resistance.

Main Results:

  • AXL upregulation is a key mechanism of resistance to anti-HER2 therapy, promoting cancer cell proliferation, survival, migration, invasion, and angiogenesis.
  • AXL signaling, particularly in conjunction with a mesenchymal phenotype, confers resistance to chemotherapy and targeted therapies.
  • Preclinical data demonstrate that AXL inhibition can restore sensitivity to HER2 blockade in breast, esophageal, and gastric cancers.
  • AXL exhibits significant potential as a prognostic and predictive biomarker in HER2-positive breast cancer.

Conclusions:

  • Co-targeting AXL and HER2 presents a promising therapeutic strategy to overcome resistance to HER2-targeted therapies.
  • AXL inhibition may be a valuable approach to re-sensitize resistant tumors to HER2-directed treatments.
  • AXL holds translational relevance as a biomarker and therapeutic target in HER2-driven cancers.
Keywords:
AXLCancerHER2 diseaseResistance

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