title: Antitumor Activity and Acquired Resistance Mechanism of Dovitinib (TKI258) in RET-Rearranged Lung Adenocarcinoma.
abstract: RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib (TKI258), a potent inhibitor of FGFR, VEGFR, and PDGFR, in RET-rearranged LADC has not been reported. The aims of the study are to explore antitumor effects and mechanisms of acquired resistance of dovitinib in RET-rearranged LADC. Using structural modeling and in vitro analysis, we demonstrated that dovitinib induced cell-cycle arrest at G0-G1 phase and apoptosis by selective inhibition of RET kinase activity and ERK1/2 signaling in RET-rearranged LC-2/ad cells. Strong antitumor effect of dovitinib was observed in an LC-2/ad tumor xenograft model. To identify the acquired resistance mechanisms to dovitinib, LC-2/ad cells were exposed to increasing concentrations of dovitinib to generate LC-2/ad DR cells. Gene-set enrichment analysis of gene expression and phosphor-kinase revealed that Src, a central gene in focal adhesion, was activated in LC-2/ad DR cells. Saracatinib, an src kinase inhibitor, suppressed ERK1/2 phosphorylation and growth of LC-2/ad DR cells. Taken together, these findings suggest that dovitinib can be a potential therapeutic option for RET-rearranged LADC, in which acquired resistance to dovitinib can be overcome by targeting Src.
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: JE-UK Institute for Cancer Research, JEUK Co. Ltd., Gumi-City, Kyungbuk, Korea.
authors.forename: Kang Won
authors.initials: KW
authors.lastname: Jang
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co. Ltd., Gumi-City, Kyungbuk, Korea.
authors.forename: Jinyoung
authors.initials: J
authors.lastname: Sohn
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co. Ltd., Gumi-City, Kyungbuk, Korea.
authors.forename: Sung-Moo
authors.initials: SM
authors.lastname: Kim
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co. Ltd., Gumi-City, Kyungbuk, Korea.
authors.forename: Kyoung-Ho
authors.initials: KH
authors.lastname: Pyo
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co. Ltd., Gumi-City, Kyungbuk, Korea.
authors.forename: Hwan
authors.initials: H
authors.lastname: Kim
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co. Ltd., Gumi-City, Kyungbuk, Korea.
authors.forename: Mi Ran
authors.initials: MR
authors.lastname: Yun
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co. Ltd., Gumi-City, Kyungbuk, Korea.
authors.forename: Han Na
authors.initials: HN
authors.lastname: Kang
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hye Ryun
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Sun Min
authors.initials: SM
authors.lastname: Lim
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Yong Wha
authors.initials: YW
authors.lastname: Moon
authors.affiliation: Division of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Soonmyung
authors.initials: S
authors.lastname: Paik
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Dae Joon
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Joo Hang
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. Institute for Cancer Research, 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: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008819:Mice, Nude; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D019061:src-Family Kinases