Insulin-like growth factor (IGF) and epidermal growth factor (EGF) receptors as therapeutic targets in metastatic renal cell carcinoma.

Abstract

e15113 Background: Renal cell carcinoma (RCC) is associated with mutation or loss of function of the von Hippel-Lindau gene resulting in hypoxia-inducible factor 1-alpha accumulation and production of growth factors involved in proliferation and angiogenesis. Radical nephrectomy remains the primary treatment option for two thirds of RCC patients who present with tumors confined to the kidney. However, approximately one half of patients will develop metastatic RCC. Treatment of RCC has been hampered by its resistance to most chemotherapy and hormonal therapy, although selected patients have long term remission from high dose of interleukin-2. Despite the recent availability of several active targeted agents in this disease, therapy is not curative. As a result, there is continued demand for improving therapy for metastatic disease to enhance both clinical benefits and patients overall survival. The EGF and IGF-1 pathways have been implicated as potential therapeutic targets in RCC. The objective of this study was to investigate the antitumor response to EGF and IGF inhibitors as a novel combination therapy in metastatic RCC. Methods: RCC cells lines (Caki-1 and Caki-2) were cultured in appropriate media supplemented with 10% FBS in a 5% CO2 incubator. Cells were treated for 24, 48, 72h, and 96h with different doses of EGFR (AG1478) and/or IGF-1R (AG1024) inhibitors (0-100 μM) given as single agent or in combination therapy. The epithelial cell proliferation was determined by AlamarBlue proliferation assay. Results: Both AG1478 and AG1024, given as single agent, decreased the epithelial cell proliferation of RCC human malignant cell lines (Caki-1 and Caki-2) (p<0.05). The inhibition occurred in a dose-dependent manner and was more pronounced at higher doses of AG1478 or AG1024 (100 μM), and when both agents were given as combination therapy. Conclusions: These data suggest that both inhibitors exhibit a synergistic antitumor effect when given as combination therapy. This synergistic benefit exhibits an anti-proliferative and pro-apoptotic effects on RCC cell lines in vitro and warrants further investigation as a potential therapeutic approach for metastatic RCC patients. No significant financial relationships to disclose.