AXL regulates mesothelioma proliferation and invasiveness

Oncogene. 2011 Apr 7;30(14):1643-52. doi: 10.1038/onc.2010.555. Epub 2010 Dec 6.

Abstract

Mesothelioma is an asbestos-associated and notoriously chemotherapy-resistant neoplasm. Activation of the receptor tyrosine kinases (RTKs), epidermal growth factor receptor and MET, has been described in subsets of mesothelioma, suggesting that TKs might represent therapeutic targets in this highly lethal disease. We employed proteomic screening by phosphotyrosine immunoaffinity purification and tandem mass spectrometry to characterize RTK activation in mesothelioma cell lines. These assays demonstrated expression and activation of the AXL protein, which is an RTK with known oncogenic properties in non-mesothelial cancer types. AXL was expressed and activated strongly in 8 of 9 mesothelioma cell lines and 6 of 12 mesothelioma biopsies, including each of 12 mesotheliomas with spindle-cell histology. Somatic AXL mutations were not found, but all mesotheliomas expressed an alternatively spliced AXL transcript with in-frame deletion of exon 10, and six of seven mesothelioma cell lines expressed the AXL ligand, growth arrest-specific 6 (GAS6). GAS6 expression appeared to be functionally relevant, as indicated by modulation of AXL tyrosine phosphorylation by knockdown of endogeneous GAS6, and by administration of exogenous GAS6. AXL silencing by lentivirus-mediated short hairpin RNA suppressed mesothelioma migration and cellular proliferation due to G1 arrest. The AXL inhibitor DP-3975 inhibited cell migration and proliferation in mesotheliomas with strong AXL activation. DP-3975 response in these tumors was characterized by inhibition of PI3-K/AKT/mTOR and RAF/MAPK signaling. AXL inhibition suppressed mesothelioma anchorage-independent growth, with reduction in colony numbers and size. These studies suggest that AXL inhibitors warrant clinical evaluation in mesothelioma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Proliferation / drug effects*
  • Exons
  • Gene Silencing
  • Humans
  • Intercellular Signaling Peptides and Proteins / isolation & purification
  • Mesothelioma / drug therapy
  • Mesothelioma / genetics*
  • Mesothelioma / pathology
  • Neoplasm Invasiveness / genetics
  • Phosphorylation
  • Pleural Neoplasms / drug therapy
  • Pleural Neoplasms / genetics*
  • Pleural Neoplasms / pathology
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Sequence Deletion
  • Signal Transduction / drug effects
  • Signal Transduction / genetics

Substances

  • Antineoplastic Agents
  • Intercellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins
  • growth arrest-specific protein 6
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase