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Oncology Research, Wyeth Pharmaceuticals, Pearl River, NY

Requests for Reprints: Lee M. Greenberger, Oncology Research, Wyeth Pharmaceuticals, Building 200, Room 4709, 401 North Middletown Road, Pearl River, NY 10965. Phone: (845) 602-3487; Fax: (845) 602-5557. E-mail: greenblm{at}wyeth.com

EKB-569 is an irreversible inhibitor of epidermal growth factor receptor (EGF-R) tyrosine kinase. It inhibits EGF-induced phosphorylation of EGF-R and the growth of tumors that overexpress EGF-R in animal models. In clinical trials, EKB-569 and all other EGF-R inhibitors cause skin rashes. To understand the latter phenomenon, the effect of EKB-569 on EGF-R as well as downstream signaling to phosphoinositide 3-kinase-protein kinase B (AKT), extracellular signal-regulated kinase 1 and 2 (ERK1/2), or signal transducer and activator of transcription 3 (STAT3) pathways were compared in tumor cell lines and normal human keratinocytes (NHEK) grown in tissue culture. Tumor cell lines that have high (A431 epidermoid and MDA-468 breast carcinomas) and low (MCF-7 breast carcinoma) expression of EGF-R were used. NHEK cells express at least 15-fold less EGF-R than A431 cells. EKB-569 was a potent inhibitor of proliferation in NHEK, A431, and MDA-468 cells (IC₅₀ = 61, 125, and 260 nM, respectively) but not MCF-7 cells (IC₅₀ = 3600 nM). EKB-569 was also a potent inhibitor of EGF-induced phosphorylated EGF-R (pEGF-R) in A431 and NHEK cells (IC₅₀ = 20–80 nM). The reduction in pEGF-R paralleled inhibition of phosphotyrosine-705 STAT3, while the inhibition of phosphorylated AKT and phosphorylated ERK1/2 occurred at higher concentrations of EKB-569 (75–500 nM) in both A431 and NHEK cells. The effects were specific because EKB-569 did not inhibit the nuclear factor-B pathway. It is proposed that skin toxicity associated with EKB-569 is due to inhibition of EGF-R signaling. Downstream signal transduction markers, particularly the activation status of STAT3, may be useful surrogate markers to guide clinical development of EGF-R inhibitors.

Received 9/ 2/03; revised 10/23/03; accepted 11/25/03.