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Animals Carcinoma, Non-Small-Cell Lung/*drug therapy Cell Line, Tumor Cell Proliferation Cytoplasm/metabolism *Drug Resistance, Neoplasm Drug Screening Assays, Antitumor/methods Gene Expression Regulation, Neoplastic Guanine Nucleotide Exchange Factors/*antagonists & inhibitors Humans Lung Neoplasms/*drug therapy Male Mice Mice, Nude Neoplasm Transplantation Quinazolines/*pharmacology Receptor, Epidermal Growth Factor/metabolism Receptor, IGF Type 1/metabolism Signal Transduction Triazoles/pharmacology
Abstract:
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib, have been proven to efficiently inhibit the proliferation of a subset of non small-cell lung cancers (NSCLC). Unfortunately, the majority of NSCLC expressing wild type EGFR is primarily resistant to EGFR-TKI treatment. Here, we show that the proliferation of the gefitinib-resistant NSCLC cell lines H460 and A549 is reduced by the small molecule SecinH3 which indirectly attenuates EGFR activation by inhibition of cytohesins, a class of recently discovered cytoplasmic EGFR activators. SecinH3 and gefitinib showed a synergistic antiproliferative effect, which correlated with a profound inhibition of Akt activation and survivin expression. Treating mice bearing H460 xenografts with SecinH3 showed the antiproliferative and pro-apoptotic effect of SecinH3 in vivo. Our data suggest that targeting the EGFR indirectly by inhibiting its cytoplasmic activators, the cytohesins, has the potential to improve the treatment of primarily EGFR-TKI resistant lung cancers.
