Analyzing the role of the novel kinase Ror2 in renal cell carcinoma

B224 Sporadic renal cell carcinoma (RCC), a notoriously hard to treat solid tumor malignancy, has minimal sensitivity to traditional chemotherapy and immune system modulation. The most current and effective therapies for renal cell carcinoma involves the use of kinase-specific inhibitors targeted against receptor tyrosine kinases (RTK) and ligands specific to angiogenesis signaling. However, though these agents have shown promise, they remain to be fully optimized. The net effect is to almost double the time to progression of RCC, with tumors eventually developing resistance to these agents. RCC is defined by inappropriate chemokine expression where, for example, platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) are highly expressed growth factors in RCC because of inactivating mutations of the von Hippel-Lindau ( VHL ) tumor suppressor gene. However, VEGF receptor and PDGF receptor, which are present on tumor-associated endothelial cells and pericytes, respectively, are not generally present on RCC tumor cells. Currently, there are no known reported cancer cell specific kinases expressed on RCC. Our goal was to identify a cancer cell specific kinase expressed on RCC as a rational target for pharmaceutical development. Using a phospho specific RTK screen in renal carcinoma cells, we identified Ror2, a phosphorylated orphan receptor tyrosine kinase previously unknown in renal carcinoma cells. Ror2 is normally expressed in the heart, brain and lungs of developing mice and has also been implicated in the Wnt/β-catenin signaling pathway. By immunoblot and qRT-PCR, we have shown that not only is Ror2 expressed in renal carcinoma cells; it is expressed in a VHL -dependent manner. In addition, we were able to detect transcripts of Ror2 in more than 55% of a set of 19 archival human RCC tumor specimens. Further analysis is currently underway to delineate the importance of Ror2 for RCC tumorigenesis and regulation as it represents a potentially important molecular target for RCC.