Enhanced Sensitivity to the HER1/Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Hydrochloride in Chemotherapy-Resistant Tumor Cell Lines

Abstract

Purpose: Erlotinib (Tarceva, OSI-774) is a potent and specific inhibitor of the HER1/epidermal growth factor receptor (EGFR) tyrosine kinase. In phase II clinical studies, oral erlotinib monotherapy has shown antitumor activity in patients with advanced non–small cell lung cancer, head and neck cancer, and ovarian cancer after the failure of standard chemotherapy. We hypothesized that some tumors treated with multiple cytotoxic therapies may become more dependent on the HER1/EGFR signaling pathways for survival. Experimental Design: The growth-inhibitory effect of erlotinib was tested on 10 pairs of chemosensitive, parental, and chemoresistant tumor cell lines. Results: Enhanced sensitivity to erlotinib was observed in the doxorubicin-resistant human breast cancer cell line MCF-7, paclitaxel-resistant human ovarian carcinoma cell line A2780, and cisplatin-resistant human cervical carcinoma cell line ME180. The IC50 values of erlotinib in the resistant cell lines were 2- to 20-fold lower than those in the corresponding parental cell lines. This enhanced sensitivity to erlotinib correlated with higher HER1/EGFR and phospho-HER1/EGFR expression when compared with the corresponding parental cell lines. Acquired resistance to cytotoxic agents was not associated with cross-resistance to erlotinib. AE-ME180/CDDP-resistant xenografts showed greater sensitivity to erlotinib than parental ME180 xenografts did. Conclusions: Our findings suggest that acquired resistance to cytotoxic therapy in some tumors is associated with enhanced sensitivity to HER1/EGFR inhibitors, which correlates with increased HER1/EGFR expression. These data may explain some of the observed clinical activity of HER1/EGFR inhibitors in patients previously treated with multiple therapies. HER1/EGFR tyrosine kinase inhibitors may be more effective as second- or third-line treatment for certain patients with tumors that were previously treated with multiple chemotherapy regimens.

RETRACTION: Erlotinib Induces Mitochondrial-Mediated Apoptosis in Human H3255 Non-Small-Cell Lung Cancer Cells with Epidermal Growth Factor ReceptorL858R Mutation through Mitochondrial Oxidative Phosphorylation-Dependent Activation of BAX and BAK

“…In previous work, we and others have demonstrated that erlotinib is a highly selective EGFR tyrosine kinase inhibitor with potent activity against human NSCLC cell lines in in vitro and in vivo studies (Moyer et al, 1997;Dai et al, 2005). We also found that erlotinib exposure caused cell growth inhibition accompanied by the cell cycle arrest at G 1 /S phase in human NSCLC cell lines.…”

SNARE-dependent interaction of Src, EGFR and β1 integrin regulates invadopodia formation and tumor cell invasion

“…Tyr845 is the only tyrosine residue in the activation loop of the EGFR (Jorissen et al, 2003), and it was recently demonstrated that high levels of the EGFR that has been phosphorylated at Tyr845 can be found in some metastatic cancers (Aquino et al, 2012). Small-molecule inhibitors and monoclonal antibodies against the EGFR that block ligandinduced EGFR autophosphorylation have been developed for therapeutic use (O'Donovan and Crown, 2007;Dai et al, 2005;von Minckwitz et al, 2005), but our observations from experiments performed in the absence of growth factors suggest an important role for EGFR signaling, independent of binding to EGF, in tumor cell invasion. Phosphorylation of the EGFR, at Tyr845 can be stimulated by Src and b1 integrin activity at sites of ECM attachment, possibly through the binding of a Src-EGFR complex to b1 integrin to promote Src activation at the plasma membrane.…”

Single-Agent and Combination Therapeutic Strategies to Inhibit Hepatocyte Growth Factor/MET Signaling in Cancer

“…Although the recent advances in the molecular knowledge of cancer shed new light on the development of selective targeted compounds, chemotherapy remains the mainstay of treatment for several malignancies. However, the use of conventional chemotherapeutic agents is frequently limited by de novo or acquired resistance, which often results from increased growth factor receptor signaling (59,60). These observations have prompted the evaluation of growth factor receptor inhibitors in combination with chemotherapy.…”