ZD1839 modulates paclitaxel response in renal cancer by blocking paclitaxel-induced activation of the epidermal growth factor receptor-extracellular signal-regulated kinase pathway

Purpose: We evaluated the antitumor activity of ZD1839, a selective epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, in combination with paclitaxel in human renal cell carcinomas (RCCs). Experimental Design: Eight human RCC lines and the surgical specimens obtained from 10 RCC patients were used. The protein expression was detected by Western blotting, immunohistochemistry and/or flow cytometry. Apoptosis was evaluated by flow cytometry and fragmented DNA ELISA. SKRC-49 tumor xenografts in athymic nude mice were treated with ZD1839 and/or paclitaxel, and tumor volume was determined. Results: EGFR protein was expressed and phosphorylated in eight RCC lines and EGFR expression was markedly increased in RCC specimens compared with adjacent normal renal tissues. Treatment of SKRC-49 with 1 muM ZD1839 resulted in a marked decrease in the phosphorylation of EGFR but not of HER-2. Treatment of SKRC-49 with ZD1839 in combination with 5 nM paclitaxel resulted in a significant increase in apoptotic cell number compared with paclitaxel alone, whereas ZD1839 alone failed to induce apoptosis. Although administration of ZD1839 or paclitaxel resulted in a transient growth inhibition in SKRC-49 xenografts, significant tumor regrowth delay was observed when paclitaxel was combined with ZD1839. Paclitaxel phosphorylated extracellular signal-regulated kinase through EGFR activation predominantly in cancer cells. ZD1839 promoted paclitaxel-induced Bcl-2 down-regulation resulting in promoting apoptosis by blocking paclitaxel-induced activation of the EGFR-extracellular signal-regulated kinase antiapoptotic pathway independent of Akt activity in SKRC-49. Conclusions: Our findings support the idea that the significant clinical benefit is obtained from ZD1839 in combination with paclitaxel for the treatment of RCC.