Kidney cancer. Principles and practice. Second edition. Primo N. Lara, Jr. Eric Jonasch (Editors). Springer International Publishing (2015)
- Role of HIF in clear cell renal carcinoma
- Cooperating events
- Treatment of renal cell carcinoma: HIF antagonists
- Treatment of renal cell carcinoma: mTOR inhibitors
- Treatment of renal cell carcinoma: angiogenesis inhibitors
- Treatment of renal cell carcinoma: tumor cell receptor tyrosine kinases
- Other targets
- Carbonic anhydrase and lactate dehydrogenase
- Histone methylases and demethylases
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 . 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 . HGF and c-MET play an important role in both tumorigenesis and angiogenesis. pVHLdefective tumor cells are hypersensitive to c-MET loss , 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 . 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  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 . 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 .
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 .
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