Requirement for the von Hippel-Lindau tumor suppressor gene for functional epidermal growth factor receptor blockade by monoclonal antibody C225 in renal cell carcinoma.
Renal cell carcinoma (RCC) is a cytologically and histologically diverse disease in which a spectrum of distinct molecular alterations occurs, including the inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene, which is specific for the clear cell variant of RCC. The prognosis for RCC is poor, and, to date, no effective systemic treatment is available for this cancer. In the present study, we assessed the extent to which the transforming growth factor alpha-epidermal growth factor receptor (EGFR) autocrine loop could be used as a potential therapeutic target for RCC. Northern blot analysis of transforming growth factor alpha and EGFR revealed variable but consistent expression of these transcripts in cell lines derived from both clear cell and non-clear cell RCC variants, indicating the potential for this autocrine loop in both tumor types. The therapeutic utility of interruption of this feedback loop was determined by examining growth inhibition after the exposure of these cell lines to a humanized anti-EGFR monoclonal antibody, C225. In vitro treatment of clear cell RCC-derived cell lines lacking VHL resulted in only a modest decrease in growth rate. In contrast, non-clear cell RCC-derived cell lines that retained VHL responded significantly to C225 treatment. Transfection of VHL into VHL-negative RCC cell lines restored responsiveness to C225, indicating that this tumor suppressor gene is required for effective EGFR blockade. Growth inhibition by C225 in VHL-positive cells was linked to a requirement for VHL to up-regulate p27 in response to C225. These data provide compelling evidence that treatment modalities for RCC are likely to be strongly influenced by the molecular etiology of this phenotypically diverse cancer.
Perera
A D
AD
The University of Texas M.D. Anderson Cancer Center, Science Park Research Division, Smithville 78957, USA.
Kleymenova
E V
EV
Walker
C L
CL
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D002452:Cell Count / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27; D066246:ErbB Receptors / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor / Q000235:genetics; D006801:Humans; D008025:Ligases; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000235:genetics; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D000911:Antibodies, Monoclonal; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D011506:Proteins; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D066246:ErbB Receptors; D008025:Ligases; C497446:VHL protein, human