Requirement for the von Hippel-Lindau tumor suppressor gene for functionalepidermal growth factor receptor blockade by monoclonal antibody C225 in renal cell carcinoma

Renal cell carcinoma (RCC) is a cytologically and histologically diverse di sease in which a spectrum of distinct molecular alterations occurs, includi ng the inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene, w hich is specific for the clear cell variant of RCC, The prognosis for RCC i s poor, and, to date, no effective systemic treatment is available for this cancer. In the present study, me assessed the extent to which the transfor ming growth factor ar-epidermal growth factor receptor (EGFR) autocrine loo p could be used as a potential therapeutic target for RCC, Northern blot an alysis of transforming growth factor cu and EGFR revealed variable but cons istent expression of these transcripts in cell lines derived from both clea r cell and non-clear cell RCC variants, indicating the potential for this a utocrine loop in both tumor types, The therapeutic utility of interruption of this feedback loop was determined by examining growth inhibition after t he exposure of these cell. Lines to a humanized anti-EGFR monoclonal antibo dy, C225. In vitro treatment of clear cell RCC-derived cell lines lacking V HL resulted in only a modest decrease in growth rate. In contrast, non-clea r cell RCC-derived cell lines that retained VHL responded significantly to C225 treatment. Transfection of VHL into VHL-negative RCC cell lines restor ed responsiveness to C225, indicating that this tumor suppressor gene is re quired for effective EGFR blockade, Growth inhibition by C225 in VHL-positi ve 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 t his phenotypically diverse cancer.