Epithelial-mesenchymal transition: A mechanism of resistance to VEGF pathway inhibition in genitourinary cancers.

Abstract

390 Background: There is emerging clinical data that epithelial-mesenchymal-transition (EMT), a cellular phenotype observed with aggressive disease and metastasis, is associated with resistance to angiogenesis inhibitors targeting the VEGF pathway. To better study and characterize this clinical observation we set out to generate well-defined preclinical prostate and kidney cancer models of EMT mediated resistance to the angiogenesis inhibitor sunitinib with the overarching goal to develop more effective antiangiogenic therapies in genitourinary malignancies. Methods: We screened a library of prostate and kidney cancer xenografts models for their response to the angiogenesis inhibitor sunitinib. By applying strict clinical criteria we identified models, which were refractory, resistant and also unambiguously sensitive to sunitinib. The sensitive cell lines were used to stably overexpress the EMT inducing transcription factors Twist1, Snail and ZEB1. The cell lines were then injected to form xenografts and their response to sunitinib was assessed. Correlative studies for microvascular density and cellularly mediated resistance through blood vessel maturation and myeloid cell recruitment were performed. Results: EMT mediated resistance to sunitinib was seen in both, prostate and kidney cancer models. Interestingly, EMT mediated resistance was primarily associated with an increase in blood vessel maturation. Conclusions: We present for the first time defined preclinical prostate and kidney cancer model of EMT mediated resistance to a multitargeted VEGF pathway inhibitor. These model could prove useful in our efforts to develop more effective antiangiogenic approaches in prostate cancer and kidney cancer and aid to predict response or the lack thereof to VEGF based therapies.