title: Anti-proliferative effect of cytohesin inhibition in gefitinib-resistant lung cancer cells.
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.
authors: Chemical Biology and Medicinal Chemistry Unit, Life and Medical Sciences (LIMES) Institute, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.
authors: Anke
authors: A
authors: Bill
authors: Anton
authors: A
authors: Schmitz
authors: Katharina
authors: K
authors: König
authors: Lukas C
authors: LC
authors: Heukamp
authors: Jeffrey S
authors: JS
authors: Hannam
authors: Michael
authors: M
authors: Famulok
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D066246:ErbB Receptors / Q000378:metabolism; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011799:Quinazolines / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction; D014230:Triazoles / Q000494:pharmacology
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D011799:Quinazolines; C516025:SecinH3; D014230:Triazoles; C577360:XH1009; C100723:cytohesin-1; C577361:secin16; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D000077156:Gefitinib