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AXL regulates mesothelioma proliferation and invasiveness

W-B Ou1, J M Corson, D L Flynn

  • 1Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Oncogene
|December 7, 2010
PubMed

Insights

AXL receptor tyrosine kinase (RTK) is activated in mesothelioma, a chemotherapy-resistant cancer. Inhibiting AXL suppressed mesothelioma growth and migration, suggesting AXL inhibitors as potential mesothelioma therapeutics.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Mesothelioma is a rare, asbestos-associated cancer known for its resistance to chemotherapy.
  • Receptor tyrosine kinases (RTKs) like EGFR and MET are implicated in mesothelioma, suggesting their potential as therapeutic targets.
  • AXL, an RTK with oncogenic roles in other cancers, was investigated for its role in mesothelioma.

Purpose of the Study:

  • To investigate the expression and activation of AXL receptor tyrosine kinase (RTK) in mesothelioma.
  • To determine the functional relevance of AXL and its ligand GAS6 in mesothelioma cell lines.
  • To evaluate the therapeutic potential of AXL inhibition in mesothelioma.

Main Methods:

  • Proteomic screening using phosphotyrosine immunoaffinity purification and tandem mass spectrometry.
  • Analysis of AXL expression and activation in mesothelioma cell lines and patient biopsies.
  • Functional studies involving AXL knockdown, GAS6 modulation, and treatment with the AXL inhibitor DP-3975.

Main Results:

  • AXL was highly expressed and activated in 8/9 mesothelioma cell lines and 6/12 mesothelioma biopsies, particularly those with spindle-cell histology.
  • An alternatively spliced AXL transcript lacking exon 10 was found in all mesotheliomas.
  • AXL inhibition by DP-3975 suppressed mesothelioma cell migration, proliferation, and anchorage-independent growth by affecting PI3-K/AKT/mTOR and RAF/MAPK signaling pathways.

Conclusions:

  • AXL is a frequently activated RTK in mesothelioma and plays a significant role in tumor growth and migration.
  • AXL signaling pathways are critical for mesothelioma cell proliferation and survival.
  • AXL inhibitors, such as DP-3975, show promise as a targeted therapy for mesothelioma and warrant clinical evaluation.

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