title: γ Secretase inhibitor BMS-708163 reverses resistance to EGFR inhibitor via the PI3K/Akt pathway in lung cancer.
abstract: Lung adenocarcinoma cells harboring epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitor (TKI). Acquired resistance to EGFR TKI develops after prolonged treatment. The aim of this study was to investigate the effect of the novel γ secretase inhibitor BMS-708163 on acquired resistance to the EGFR TKI gefitinib. We did not observe known mechanisms of acquired resistance to EGFR TKI, including the EGFR T790M mutation and MET gene amplification in the gefitinib-resistant PC9/AB2 cells. BMS-708163 inhibited PI3K/Akt expression and sensitized PC9/AB2 cells to gefitinib-induced cytotoxicity. In contrast, BMS-708163 had no significant effect on gefitinib sensitivity in PC9 parental cells. Combined treatment with BMS-708163 and gefitinib induced high levels of apoptosis. Our in vivo studies showed that combined treatment of gefitinib and BMS-708163 inhibited the growth of PC9/AB2 xenografts. In conclusion, our data show that combined treatment of gefitinib and γ secretase inhibitors may be useful for treating lung adenocarcinomas harboring EGFR mutations with acquired gefitinib resistance.
authors.affiliation: China State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, 151 Yan Jiang Road, Guangzhou, 510120, China.
authors.forename: Mian
authors.initials: M
authors.lastname: Xie
authors.forename: Jianxing
authors.initials: J
authors.lastname: He
authors.forename: Chaosheng
authors.initials: C
authors.lastname: He
authors.forename: Shenhai
authors.initials: S
authors.lastname: Wei
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D000077156:Gefitinib; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D010069:Oxadiazoles / Q000627:therapeutic use*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011799:Quinazolines / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*
chemical_list: C554092:BMS 708163; D010069:Oxadiazoles; D011799:Quinazolines; D013449:Sulfonamides; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D053829:Amyloid Precursor Protein Secretases; D000077156:Gefitinib
keywords: DRUG RESISTANCE; GEFITINIB; LUNG CANCER; γ SECRETASE INHIBITOR