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|Ref Type||Journal Article|
|Authors||Nilsson MB, Giri U, Gudikote J, Tang X, Lu W, Tran H, Fan Y, Koo A, Diao L, Tong P, Wang J, Herbst R, Johnson BE, Ryan A, Webster A, Rowe P, Wistuba II, Heymach JV|
|Title||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.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2016 Apr 15|
|Abstract Text||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.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.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.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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|KDR||NCBI||CD309|FLK1|VEGFR|VEGFR2||KDR (VEGFR2), kinase insert domain receptor, is also known as vascular endothelial growth factor receptor 2 and is an endothelial cell surface receptor tyrosine kinase and member of the vascular endothelial growth factor family of proteins that plays a role in angiogenesis and cell proliferation through activation of RAF-MEK-MAP and PI3K-AKT pathways (PMID: 25568876, PMID: 29093528, PMID: 26578684). KDR amplification and overexpression have been reported in a variety of tumor types (PMID: 21382095, PMID: 27218826, PMID: 25231439, PMID: 20606037, PMID: 30819137) and somatic mutations have been reported in sarcomas and head and neck squamous cell carcinomas (PMID: 22314185, PMID: 11801954).||Oncogene|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|KDR amp||lung non-small cell carcinoma||no benefit||Vandetanib||Phase III||Actionable||In a retrospective analysis of a Phase III trial, treatment with Caprelsa (vandetanib) did not correlate with an improved PFS, OS, or objective response rate in non-small cell lung carcinoma patients harboring a KDR amplification nor did it inhibit cell proliferation of the KDR amplified archived tumor cells in culture (PMID: 26578684).||26578684|