Targeting TR4-induced RCC cells-derived exosomally initiated signaling increases Sunitinib efficacy

Sunitinib is the first-line therapy for metastatic clear cell renal cell carcinoma (RCC) via suppressing neoangiogenesis and tumor growth. The detailed mechanisms, especially whether and how RCC cells can impact endothelial cells sensitivity to Sunitinib, remain unclear. Here, we found that TR4 was commonly upregulated in RCC tissue and relative to tumor angiogenesis. Tube formation and Mouse aortic ring assay showed that the overexpression or knockdown of TR4 in RCC cells enhanced or reduced the angiogenesis of endothelial cells and their resistance to Sunitinib in vitro. Mechanistically, We found that TR4 transcriptionally increase ADAM15 expression, as a consequence, exosomes carrying relatively large amounts of ADAM15 secreted from RCC cell resulted in activating the EGFR phosphorylation and reducing the efficacy of Sunitinib in endothelial cells. Targeting the TR4-induced renal cancers-derived exosomelly initiated signaling with a small molecular, CRM197, increases sunitinib efficacy in vitro and xenograft tumor models. Taken together, our findings indicate a novel function of TR4 in RCC blunted the efficacy of sunitinib via exosomal ADAM15-induced activation of EGFR signaling pathway in endothelial cells.