Targeting the epidermal growth factor receptor by erlotinib (Tarceva™) for the treatment of esophageal cancer

Abstract

Esophageal cancer is the sixth most common cause of cancerrelated death worldwide. Because of very poor 5-year survival new therapeutic approaches are mandatory. Erlotinib (Tarceva TM ), an inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TK), potently suppresses the growth of various tumors but its effect on esophageal carcinoma, known to express EGFR, remains unexplored. We therefore studied the antineoplastic potency of erlotinib in human esophageal cancer cells. Erlotinib induced growth inhibition of the human esophageal squamous cell carcinoma (ESCC) cell lines Kyse-30, Kyse-70 and Kyse-140, and the esophageal adenocarcinoma cell line OE-33, as well as of primary cell cultures of human esophageal cancers. Combining erlotinib with the EGFR-receptor antibody cetuximab, the insulin-like growth factor receptor tyrosine kinase inhibitor tyrphostin AG1024, or the 3-hydroxy-3-methylglutaryl coenzyme. A reductase (HMG-CoAR) inhibitor fluvastatin resulted in additive or even synergistic antiproliferative effects. Erlotinib induced cell cycle arrest at the G1/S checkpoint. The erlotinib-mediated signaling involved the inactivation of EGFR-TK and ERK1/2, the upregulation of the cyclindependent kinase inhibitors p21 Waf1/CIP1 and p27 Kip1, and the downregulation of the cell cycle promoter cyclin D1. However, erlotinib did not induce immediate cytotoxicity or apoptosis in esophageal cancer cells. The inhibition of EGFR-TK by erlotinib appears to be a promising novel approach for innovative treatment strategies of esophageal cancer, as it powerfully induced growth inhibition and cell cycle arrest in human esophageal cancer cells and enhanced the antineoplastic effects of other targeted agents. ' 2005 Wiley-Liss, Inc.

Isolation and characterization of erlotinib-resistant human non-small cell lung cancer A549 cells

“…p21 plays an essential role in growth arrest after DNA damage, while its overexpression leads to cell cycle arrest, which prevents DNA damage (17). Erlotinib-mediated signaling is involved in the up-regulation of p21 (18). We demonstrated the overexpression of p21 in erlotinib-resistant cells (A549/ ER cells) when compared to A549 cells (Fig.…”

Pilot Study of Neoadjuvant Treatment with Erlotinib in Nonmetastatic Head and Neck Squamous Cell Carcinoma

“…We also showed that tumor p21 waf immunostaining at baseline was correlated with clinical response to neoadjuvant erlotinib. In squamous cell carcinoma cell lines, the cytostatic effect of erlotinib is mediated by p21 waf (26). Furthermore, it has been reported that loss of p21 waf expression is correlated with poor prognosis in squamous cell carcinoma (27).…”

Combined Targeting of Epidermal Growth Factor Receptor, Signal Transducer and Activator of Transcription-3, and Bcl-XLEnhances Antitumor Effects in Squamous Cell Carcinoma of the Head and Neck

“…UM-22B, PCI-15B, and 1483 cells were treated with a range of doses of the inhibitors for 72 h, and MTT assays were performed to assess cell viability. The time point and range of doses used were selected based on kinetics experiments (data not shown) and previously published reports Seki et al, 2006;Sutter et al, 2006). Data were normalized to untreated control cells, and the percentage of cytotoxicity and IC 50 values were calculated as described under Materials and Methods.…”