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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.

Original publication

DOI

10.1158/1078-0432.CCR-15-1994

Type

Journal article

Journal

Clin Cancer Res

Publication Date

15/04/2016

Volume

22

Pages

1940 - 1950

Keywords

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