Soluble AXL as a marker of disease progression and survival in melanoma

PLoS One. 2020 Jan 9;15(1):e0227187. doi: 10.1371/journal.pone.0227187. eCollection 2020.

Abstract

Receptor tyrosine kinase AXL is a one-pass transmembrane protein upregulated in cancers and associated with lower survival and therapy resistance. AXL can be cleaved by the A Disintegrin and Metalloproteinases (ADAM)10 and ADAM17, yielding a soluble version of the protein. Elevated soluble AXL (sAXL) has been reported to be associated with disease progression in hepatocellular carcinoma, renal cancer, neurofibromatosis type 1 and inflammatory diseases. In the present work, we analyzed sAXL levels in blood from melanoma patients and showed that sAXL increases with disease progression. Additionally, increased sAXL levels were found correlated with shorter two-year survival in stage IV patients treated with ipilimumab. Furthermore, we showed that sAXL levels were related to the percentage of cells expressing AXL in resected melanoma lymph node metastases. This finding was verified in vitro, where sAXL levels in the cell media corresponded to AXL expression in the cells. AXL inhibition using the small-molecular inhibitor BGB324 reduced sAXL levels, while the cellular expression was elevated through increased protein stability. Our findings signify that quantification of sAXL blood levels is a simple and easily assessable method to determine cellular AXL levels and should be further evaluated for its use as a biomarker of disease progression and treatment response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Immunological / adverse effects
  • Antineoplastic Agents, Immunological / therapeutic use
  • Axl Receptor Tyrosine Kinase
  • Benzocycloheptenes / pharmacology
  • Biomarkers, Tumor / blood
  • Cell Line, Tumor
  • Disease Progression*
  • Female
  • Humans
  • Ipilimumab / adverse effects
  • Ipilimumab / therapeutic use
  • Male
  • Melanoma / blood*
  • Melanoma / drug therapy
  • Melanoma / mortality*
  • Melanoma / pathology
  • Middle Aged
  • Neoplasm Staging
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / blood*
  • Proto-Oncogene Proteins / chemistry
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / blood*
  • Receptor Protein-Tyrosine Kinases / chemistry
  • Skin Neoplasms / blood*
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / mortality*
  • Skin Neoplasms / pathology
  • Solubility
  • Survival Rate
  • Triazoles / pharmacology

Substances

  • Antineoplastic Agents, Immunological
  • Benzocycloheptenes
  • Biomarkers, Tumor
  • Ipilimumab
  • Proto-Oncogene Proteins
  • Triazoles
  • bemcentinib
  • Receptor Protein-Tyrosine Kinases
  • Axl Receptor Tyrosine Kinase
  • AXL protein, human

Grant support

This work was supported by the following grants: KFK, EM: Southern and Eastern Norway Regional Health Authority (Project number 39873) and MN: Bodil and Magnes Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.