Differential regulation of sunitinib targets predicts its tumor-type-specific effect on endothelial and/or tumor cell apoptosis

Cancer Chemother Pharmacol. 2013 Dec;72(6):1183-93. doi: 10.1007/s00280-013-2300-0. Epub 2013 Sep 24.

Abstract

Purpose: Sunitinib is an inhibitor of tyrosine-kinase receptors, and no biomarker predictive of sunitinib response is available. The purpose of this preclinical study was to show whether sunitinib molecular targets could be used as biomarkers to assess tumor response to sunitinib in human cancer cell line xenografts of three different tumor types.

Methods: Using mice xenografted with liver, breast and renal carcinoma cell lines, we sequentially analyzed the effect of 7-day sunitinib treatment on tumor and vascular compartments.

Results: In all xenografts, microvessel damage occurred from Day 1. Tumor damage also occurred in liver, breast, but not in renal xenografts. Using specific human and mouse probes for genes encoding sunitinib targets, we showed a significant relation between apoptotic tumor cell numbers and human PDGFRΒ and RET mRNA expression in liver cancer and to human VEGFR2 expression in breast cancer xenografts. In contrast, in renal cancer xenografts, vascular effect evaluated by measuring endothelial cell apoptosis was related to mouse Vegfr1, Vegfr2 and Vegfa-164 expression.

Conclusion: This study identifies sunitinib vascular and tumor effects according to different tumor types and shows that sunitinib molecular targets used as biomarkers enable assessment of therapeutic response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / pathology
  • Carcinoma, Renal Cell / drug therapy
  • Carcinoma, Renal Cell / pathology
  • Cell Line, Tumor
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Female
  • Humans
  • Indoles / pharmacology*
  • Kidney Neoplasms / drug therapy
  • Kidney Neoplasms / pathology
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / pathology
  • Mice
  • Mice, Nude
  • Molecular Targeted Therapy
  • Pyrroles / pharmacology*
  • Sunitinib
  • Xenograft Model Antitumor Assays

Substances

  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Indoles
  • Pyrroles
  • Sunitinib