Expression and role of TYRO3 and AXL as potential therapeutical targets in leiomyosarcoma

Br J Cancer. 2017 Dec 5;117(12):1787-1797. doi: 10.1038/bjc.2017.354. Epub 2017 Oct 12.

Abstract

Background: Leiomyosarcoma (LMS) are 15% of adult sarcomas and remain seldom curable in metastatic phase. The TAM receptors and their ligands are overexpressed or activated in multiple malignancies, including LMS.

Methods: The TAM receptor and ligand expression was evaluated in LMS cell lines and 358 sarcoma samples by either gene expression or immunohistochemistry. TYRO3 and AXL were knocked down. Crizotinib and foretinib were investigated in vitro.

Results: High expression of TYRO3 and AXL was detected in LMS cell lines. TYRO3 or AXL gene knockdown reduced cell proliferation/colony formation. Crizotinib and foretinib decreased TYRO3 and AXL phosphorylation, apoptosis, G2/arrest and reduced colony formation. Immunohistochemistry performed in 107 sarcomas showed higher expression of TYRO3 and GAS6 in LMS vs other sarcomas and nuclear TYRO3 only in LMS. Microarray gene expression performed in 251 sarcomas revealed significantly higher expression of TYRO3 and GAS6 in LMS than other sarcomas. Leiomyosarcoma patients with high expression of GAS6 or PROS1 present a significantly worse PFS.

Conclusions: Leiomyosarcoma patients, especially those whom develop metastasis, express higher levels of TYRO3 and GAS6. Crizotinib and foretinib showed effective antitumour activity in LMS through TYRO3 and AXL deactivation indicating that clinical trials using TYRO3 and AXL inhibitors are warranted in advanced LMS.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Anilides / pharmacology*
  • Apoptosis / drug effects
  • Blood Proteins / genetics
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Proliferation / genetics
  • Crizotinib
  • Disease-Free Survival
  • Female
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Gene Expression
  • Gene Silencing
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Leiomyosarcoma / drug therapy*
  • Leiomyosarcoma / genetics
  • Leiomyosarcoma / secondary
  • Male
  • Middle Aged
  • Phosphorylation / drug effects
  • Primary Cell Culture
  • Protein S
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism*
  • Pyrazoles / pharmacology*
  • Pyridines / pharmacology*
  • Quinolines / pharmacology*
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Tumor Stem Cell Assay
  • Young Adult

Substances

  • Anilides
  • Blood Proteins
  • GSK 1363089
  • Intercellular Signaling Peptides and Proteins
  • PROS1 protein, human
  • Protein S
  • Proto-Oncogene Proteins
  • Pyrazoles
  • Pyridines
  • Quinolines
  • growth arrest-specific protein 6
  • Crizotinib
  • Receptor Protein-Tyrosine Kinases
  • TYRO3 protein, human
  • axl receptor tyrosine kinase