title: EGFR-Mediated Reactivation of MAPK Signaling Induces Acquired Resistance to GSK2118436 in BRAF V600E-Mutant NSCLC Cell Lines.
abstract: Although treatment of BRAF V600E-mutant non-small cell lung cancer (NSCLC(V600E)) with GSK2118436 has shown an encouraging efficacy, most patients develop resistance. To investigate the mechanisms of acquired resistance to GSK2118436 in NSCLC(V600E), we established GSK2118436-resistant (GSR) cells by exposing MV522 NSCLC(V600E) to increasing GSK2118436 concentrations. GSR cells displayed activated EGFR-RAS-CRAF signaling with upregulated EGFR ligands and sustained activation of ERK1/2, but not MEK1/2, in the presence of GSK2118436. Treatment of GSR cells with GSK2118436 enhanced EGFR-mediated RAS activity, leading to the formation of BRAF-CRAF dimers and transactivation of CRAF. Interestingly, sustained activation of ERK1/2 was partly dependent on receptor-interacting protein kinase-2 (RIP2) activity, but not on MEK1/2 activity. Combined BRAF and EGFR inhibition blocked reactivation of ERK signaling and improved efficacy in vitro and in vivo Our findings support the evaluation of combined BRAF and EGFR inhibition in NSCLC(V600E) with acquired resistance to BRAF inhibitors. Mol Cancer Ther; 15(7); 1627-36. ©2016 AACR.
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi, Kyungbuk, Korea.
authors.forename: Sung-Moo
authors.initials: SM
authors.lastname: Kim
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi, Kyungbuk, Korea.
authors.forename: Hwan
authors.initials: H
authors.lastname: Kim
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi, Kyungbuk, Korea.
authors.forename: Kang Won
authors.initials: KW
authors.lastname: Jang
authors.affiliation: Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Min Hwan
authors.initials: MH
authors.lastname: Kim
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi, Kyungbuk, Korea.
authors.forename: Jinyoung
authors.initials: J
authors.lastname: Sohn
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi, Kyungbuk, Korea.
authors.forename: Mi Ran
authors.initials: MR
authors.lastname: Yun
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi, Kyungbuk, Korea.
authors.forename: Han Na
authors.initials: HN
authors.lastname: Kang
authors.affiliation: Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Chan Woo
authors.initials: CW
authors.lastname: Kang
authors.affiliation: Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hye Ryun
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Sun Min
authors.initials: SM
authors.lastname: Lim
authors.affiliation: Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Yong Wha
authors.initials: YW
authors.lastname: Moon
authors.affiliation: Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Joo Hang
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Division of Pathology NSABP, Pittsburgh, Pennsylvania. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Soonmyung
authors.initials: S
authors.lastname: Paik
authors.affiliation: Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea. cbc1971@yuhs.ac.
authors.forename: Byoung Chul
authors.initials: BC
authors.lastname: Cho
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D019898:Autocrine Communication; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003062:Codon; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D010091:Oximes / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003062:Codon; D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D048493:Proto-Oncogene Proteins B-raf; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; C561627:dabrafenib