@entity319 Amplification Is Associated with XXXX -Induced Activation of the @entity3470 and Invasion Pathways but does not Predict Clinical Benefit to the @entity319 TKI @entity4733 .

@entity1 @entity7738 @entity7 @entity5 @entity1149 @entity2 @entity1205 @entity319 @entity3470 @entity4733 @entity1435 @entity4149 @entity902
PURPOSE: @entity7 pathway inhibitors have been investigated as therapeutic agents in the treatment of @entity1149 ( @entity1149 ) because of its central role in angiogenesis. These agents have improved survival in @entity1 with advanced @entity1149 , but the effects have been modest. Although @entity319 /KDRis typically localized to the vasculature, amplification ofKDRhas reported to occur in 9% to 30% of the DNA from different @entity2 . We investigated the signaling pathways activated downstream ofKDRand whetherKDRamplification is associated with benefit in @entity1 with @entity1149 treated with the @entity319 inhibitor @entity4733 . METHODS: @entity1149 cell lines with or withoutKDRamplification were studied for the effects of @entity319 @entity4149 kinase inhibitors (TKI) on cell viability and migration. @entity5 samples collected from @entity1 with @entity902 -refractory @entity1149 in the phase III ZODIAC study of @entity4733 plus @entity1205 or placebo plus @entity1205 (N= 294) were screened forKDRamplification by FISH. RESULTS: KDRamplification was associated with @entity7 -induced activation of @entity3470 , @entity1435 , and invasiveness in @entity1149 cell lines. However, @entity319 TKIs did not inhibit proliferation of @entity1149 cell lines withKDRamplification. @entity319 inhibition decreased cell motility as well as expression of @entity7738 inKDR-amplified @entity1149 cells. In the ZODIAC study,KDRamplification was observed in 15% of @entity1 and was not associated with improved progression-free survival, overall survival, or objective response rate for the @entity4733 arm. CONCLUSIONS: Preclinical studies suggestKDRactivates invasion but not survival pathways inKDR-amplified @entity1149 models. @entity1 with @entity1149 whose @entity5 hadKDRamplification were not associated with clinical benefit for @entity4733 in combination with @entity1205 .Clin Cancer Res; 22(8); 1940-50.   2015 AACR.
