Upregulated stromal EGFR and vascular remodeling in @entity19 xenograft models of @entity7499 inhibitor-resistant XXXX @entity2220 .

@entity1 @entity7499 @entity7 @entity5 @entity19 @entity470 @entity3 @entity2220
Angiogenesis is critical for @entity5 growth and @entity3 , and several inhibitors of @entity7499 are currently in clinical use for the treatment of @entity5 . However, not all @entity1 benefit from antiangiogenic therapy, and those @entity5 that initially respond to treatment ultimately become resistant. The mechanisms underlying this, and the relative contributions of @entity5 cells and stroma to resistance, are not completely understood. Here, using species-specific profiling of @entity19 xenograft models of @entity1 @entity2220 , we have shown that gene expression changes associated with acquired resistance to the @entity7 inhibitor bevacizumab occurred predominantly in stromal and not @entity5 cells. In particular, components of the @entity470 and FGFR pathways were upregulated in stroma, but not in @entity5 cells. Increased activated @entity470 was detected on pericytes of xenografts that acquired resistance and on endothelium of @entity5 with relative primary resistance. Acquired resistance was associated with a pattern of pericyte-covered, normalized revascularization, whereas tortuous, uncovered vessels were observed in relative primary resistance. Importantly, dual targeting of the @entity7 and @entity470 pathways reduced pericyte coverage and increased progression-free survival. These findings demonstrated that alterations in @entity5 stromal pathways, including the @entity470 and FGFR pathways, are associated with, and may contribute to, resistance to @entity7 inhibitors and that targeting these pathways may improve therapeutic efficacy. Understanding stromal signaling may be critical for developing biomarkers for @entity7499 inhibitors and improving combination regimens.
