Treatment of renal cell carcinoma: tumor cell receptor tyrosine kinases

Kidney cancer. Principles and practice. Second edition. Primo N. Lara, Jr. Eric Jonasch (Editors). Springer International Publishing (2015)


Renal cell carcinomas frequently overexpress EGFR and its ligand TGFα [233–236]. TGFα is a transcriptional HIF target, while HIF has been reported to increase the rate of EGFR translation [97, 237, 238]. In addition, pVHL loss might decrease the rate of EGFR internalization and recycling [129]. In preclinical models, inhibiting EGFR decreases tumor growth in vivo [239, 240].

Despite these observations, EGFR inhibitors have been very disappointing in the treatment of renal cell carcinoma, both alone and in combination with VEGF inhibitors [241, 242]. Why have EGFR inhibitors failed thus far in the clinic? One possibility, in addition to a possible failure to achieve adequate EGFR inhibition in vivo, stems from recent work showing that c-MET, which is frequently active in renal cell carcinoma (see below), can confer resistance to EGFR blockade [243–245]. Preclinical xenograft studies performed in mice frequently underestimate the importance of c-MET because mouse HGF, the ligand for c-MET, does not activate human c-MET (present on implanted human tumor cells) [246, 247].


pVHL-defective tumor cells exhibit increased c-MET activity and are hypersensitive to HGF [248–250]. Precisely how pVHL regulates c-MET is somewhat controversial, with some report suggesting c-MET is a HIF target [250–252] and others focusing on the effects of pVHL on signaling downstream of c-MET [248, 249]. Interestingly, activating germline MET mutations are linked to the development of papillary renal cell carcinoma [253]. HGF and c-MET play an important role in both tumorigenesis and angiogenesis. pVHLdefective tumor cells are hypersensitive to c-MET loss [254], and inhibition of c-MET might, for the reasons outlined above, augment the activity of EGFR inhibitors. Cabozantinib (XL184), which inhibits both VEGFR and c-MET, demonstrated clinical activity in heavily pretreated renal cell carcinoma patients who had failed prior VEGF inhibitor therapy in a phase 1 study [255]. To what extent these responses were due specifically to c-Met inhibition remains to be determined.


HIF upregulates IGF-1 and IGF-2 as well as IGFB-2 and IGFB-3 [256, 257]. pVHL, in a HIFindependent manner, downregulates IGFR levels by inhibiting SP1 and the RNA-binding protein HuR [134] and IGFR-dependent signaling through PKCd [123, 124]. Inhibition of IGFR sensitizes renal cell carcinoma cells to cytotoxic drugs as well as to rapamycin-like drugs [258]. This latter observation might relate to the role of rapamycin in feedback inhibition of receptor tyrosine kinase signaling, as described above. In addition, downregulation of IGFR-1 with shRNA technology decreases VHL-/renal carcinoma growth in nude mouse xenograft assays [259].


ROR2 (RTK-like orphan receptor 2) was identified in an unbiased screen for receptor tyrosine kinases that are upregulated and activated by pVHL loss in renal carcinoma cells [260, 261]. The biological functions of ROR2 are incompletely understood although it has been linked to tumor cell invasiveness through the upregulation of matrix metalloproteinases and may act as a receptor for Wnt ligands. Inhibition of ROR2 in renal carcinoma cells with short hairpin RNAs suppresses tumor growth in orthotopic tumor models [261].

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