KDR Amplification Is Associated with VEGF-Induced Activation of the mTOR and Invasion Pathways but does not Predict Clinical Benefit to the VEGFR TKI Vandetanib

Clin Cancer Res. 2016 Apr 15;22(8):1940-50. doi: 10.1158/1078-0432.CCR-15-1994. Epub 2015 Nov 17.

Abstract

Purpose: VEGF pathway inhibitors have been investigated as therapeutic agents in the treatment of non-small cell lung cancer (NSCLC) because of its central role in angiogenesis. These agents have improved survival in patients with advanced NSCLC, but the effects have been modest. Although VEGFR2/KDRis typically localized to the vasculature, amplification ofKDRhas reported to occur in 9% to 30% of the DNA from different lung cancers. We investigated the signaling pathways activated downstream ofKDRand whetherKDRamplification is associated with benefit in patients with NSCLC treated with the VEGFR inhibitor vandetanib.

Methods: NSCLC cell lines with or withoutKDRamplification were studied for the effects of VEGFR tyrosine kinase inhibitors (TKI) on cell viability and migration. Archival tumor samples collected from patients with platinum-refractory NSCLC in the phase III ZODIAC study of vandetanib plus docetaxel or placebo plus docetaxel (N= 294) were screened forKDRamplification by FISH.

Results: KDRamplification was associated with VEGF-induced activation of mTOR, p38, and invasiveness in NSCLC cell lines. However, VEGFR TKIs did not inhibit proliferation of NSCLC cell lines withKDRamplification. VEGFR inhibition decreased cell motility as well as expression of HIF1α inKDR-amplified NSCLC cells. In the ZODIAC study,KDRamplification was observed in 15% of patients and was not associated with improved progression-free survival, overall survival, or objective response rate for the vandetanib arm.

Conclusions: Preclinical studies suggestKDRactivates invasion but not survival pathways inKDR-amplified NSCLC models. Patients with NSCLC whose tumor hadKDRamplification were not associated with clinical benefit for vandetanib in combination with docetaxel.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / mortality
  • Piperidines / pharmacology*
  • Piperidines / therapeutic use
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-met / metabolism
  • Quinazolines / pharmacology*
  • Quinazolines / therapeutic use
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism*
  • Treatment Outcome
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Piperidines
  • Protein Kinase Inhibitors
  • Quinazolines
  • Vascular Endothelial Growth Factor A
  • Proto-Oncogene Proteins c-met
  • Vascular Endothelial Growth Factor Receptor-2
  • TOR Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases
  • vandetanib