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
Summary
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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