title: LXR ligands sensitize EGFR-TKI-resistant human lung cancer cells in vitro by inhibiting Akt activation.
abstract: Lung adenocarcinoma cells harboring epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs). Prolonged cancer treatment will induce the development of acquired resistance to EGFR TKI. Here we investigate the effects of two novel liver x receptor (LXR) ligands (T0901317 or GW3965) on the development of acquired resistance to an EGFR TKI gefitinib. We observed known mechanisms of acquired resistance to EGFR TKI, including the EGFR T790M mutation, MET gene amplification and loss of PTEN in the gefitinib-resistant HCC827-8-1 cells. However, we found expression of MET was lower in HCC827-8-1 cells than in HCC827 cells. T0901317 or GW3965 inhibited Akt activation and sensitized HCC827-8-1 cells to gefitinib-induced cytotoxicity. In contrast, LXR ligands alone had no significant effect on HCC827-8-1 cells. In conclusion, this combined treatment may be of interest for treatment of lung adenocarcinomas harboring EGFR mutations and acquired resistance to gefitinib.
authors.affiliation: The First Clinical School of Nanjing Medical University, Nanjing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.affiliation: The First Clinical School of Nanjing Medical University, Nanjing, China.
authors.forename: Dan-dan
authors.initials: DD
authors.lastname: Yu
authors.affiliation: The Fourth Clinical School of Nanjing Medical University, Nanjing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Chemotherapy, Nanjing Medical University Affiliated Cancer Hospital Cancer Institute of Jiangsu Province, Nanjing, China.
authors.forename: Hai-xia
authors.initials: HX
authors.lastname: Cao
authors.affiliation: Department of Chemotherapy, Nanjing Medical University Affiliated Cancer Hospital Cancer Institute of Jiangsu Province, Nanjing, China.
authors.forename: Shao-rong
authors.initials: SR
authors.lastname: Yu
authors.affiliation: The Fourth Clinical School of Nanjing Medical University, Nanjing, China.
authors.forename: Si-wen
authors.initials: SW
authors.lastname: Liu
authors.affiliation: Department of Chemotherapy, Nanjing Medical University Affiliated Cancer Hospital Cancer Institute of Jiangsu Province, Nanjing, China. Electronic address: jifengfeng187@163.com.
authors.forename: Ji-feng
authors.initials: JF
authors.lastname: Feng
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D000077156:Gefitinib; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D000071518:Liver X Receptors; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D009154:Mutation; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology
chemical_list: D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib
keywords: Drug resistance; Gefitinib; LXR; Lung cancer