title: A novel treatment strategy for EGFR mutant NSCLC with T790M-mediated acquired resistance.
abstract: The purpose of our study was to identify novel kinase inhibitors for the treatment of genetic subsets of non-small cell lung cancer (NSCLC). NSCLC cell lines (n = 8) with known oncogenic backgrounds (K-Ras, EGFR and EML4-ALK) were exposed to several kinase inhibitors and analyzed for cell growth/cytotoxicity and signaling. Gö6976, a classical protein kinase C inhibitor, showed high potency against mutated EGFR and was further validated in vitro using additional NSCLC lines (n = 4) and Ba/F3 models and in vivo using a xenograft model. Gö6976 was identified to be a potent inhibitor of mutated EGFR with IC50 values from 0.033 nM to 3.3 μM and down regulating phosphorylation of EGFR, AKT and ERK1/2 at concentrations in the range of the IC(50)  values. Gö6976 has only a minor effect on wild-type EGFR and cell lines independent of signaling from the mutant EGFR. Most importantly, the activity of Gö6976 remains unchanged despite the presence of the T790M-mediated resistance, and it prevents the occurrence of this resistance in vitro. Gö6976 was also shown to significantly reduce tumor growth in an in vivo xenograft model with a EGFR-mutated NSCLC cell line containing T790M. These findings demonstrate that Gö6976 acts as a potent inhibitor of mutant EGFR despite the presence of T790M, the most important mechanism of acquired resistance for EGFR tyrosine kinase inhibitors, in both in vitro and in vivo models.
authors.affiliation: Department of Medical Oncology and Radiotherapy, Oulu University Hospital, Oulu, Finland.
authors.forename: Erika
authors.initials: E
authors.lastname: Taube
authors.forename: Elina
authors.initials: E
authors.lastname: Jokinen
authors.forename: Peppi
authors.initials: P
authors.lastname: Koivunen
authors.forename: Jussi P
authors.initials: JP
authors.lastname: Koivunen
mesh_terms: D002227:Carbazoles / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000235:genetics*; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009154:Mutation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*
chemical_list: D002227:Carbazoles; D004791:Enzyme Inhibitors; C081021:Go 6976; D066246:ErbB Receptors; D011493:Protein Kinase C