title: Gefitinib-resistance is related to BIM expression in non-small cell lung cancer cell lines.
abstract: Recent evidence indicates that both the phosphatidylinositol 3-kinase (PI3K)/AKT and the MEK/ERK pathways are strictly regulated by epidermal growth factor receptor in non-small cell lung cancer (NSCLC) that responds to Gefitinib. Gefitinib resistance is partly owing to the activation of two major downstream signaling pathways PI3K/AKT or MEK/ERK. In this study, we found that in Gefitinib-sensitive cell lines, Gefitinib could induce tumor cell apoptosis via upregulation of a proapoptotic protein BIM. Small interfering RNA results showed that silencing of BIM could alleviate apoptosis induced by Gefitinib. We adopted a combination of PI3K inhibitor (LY294002) and MEK inhibitor (U0126) against Gefitinib resistance in cell lines. As expected, the combination substantially induced apoptosis and restored the sensitivity to Gefitinib by increasing the expression of BIM. Our studies provided a theoretical basis for overcoming drug resistance in NSCLC via combination therapy.
authors.affiliation: Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Heyan
authors.initials: H
authors.lastname: Li
authors.forename: Songwen
authors.initials: S
authors.lastname: Zhou
authors.forename: Xuefei
authors.initials: X
authors.lastname: Li
authors.forename: Daoyuan
authors.initials: D
authors.lastname: Wang
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Wang
authors.forename: Caicun
authors.initials: C
authors.lastname: Zhou
authors.forename: Gerald
authors.initials: G
authors.lastname: Schmid-Bindert
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D000077156:Gefitinib; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D004791:Enzyme Inhibitors; D000077156:Gefitinib; D020930:MAP Kinase Kinase Kinases; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D034741:RNA, Small Interfering; C000606775:BCL2L11 protein, human