title: In vivo imaging models of bone and brain metastases and pleural carcinomatosis with a novel human EML4-ALK lung cancer cell line.
abstract: EML4-ALK lung cancer accounts for approximately 3-7% of non-small-cell lung cancer cases. To investigate the molecular mechanism underlying tumor progression and targeted drug sensitivity/resistance in EML4-ALK lung cancer, clinically relevant animal models are indispensable. In this study, we found that the lung adenocarcinoma cell line A925L expresses an EML4-ALK gene fusion (variant 5a, E2:A20) and is sensitive to the ALK inhibitors crizotinib and alectinib. We further established highly tumorigenic A925LPE3 cells, which also have the EML4-ALK gene fusion (variant 5a) and are sensitive to ALK inhibitors. By using A925LPE3 cells with luciferase gene transfection, we established in vivo imaging models for pleural carcinomatosis, bone metastasis, and brain metastasis, all of which are significant clinical concerns of advanced EML4-ALK lung cancer. Interestingly, crizotinib caused tumors to shrink in the pleural carcinomatosis model, but not in bone and brain metastasis models, whereas alectinib showed remarkable efficacy in all three models, indicative of the clinical efficacy of these ALK inhibitors. Our in vivo imaging models of multiple organ sites may provide useful resources to analyze further the pathogenesis of EML4-ALK lung cancer and its response and resistance to ALK inhibitors in various organ microenvironments.
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nanjo
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Shinji
authors.initials: S
authors.lastname: Takeuchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Kita
authors.forename: Koji
authors.initials: K
authors.lastname: Fukuda
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Nakada
authors.forename: Hisanori
authors.initials: H
authors.lastname: Uehara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishihara
authors.forename: Eiji
authors.initials: E
authors.lastname: Hara
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Uramoto
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Tanaka
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000556:secondary; D001932:Brain Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000556:secondary; D002227:Carbazoles / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D000077547:Crizotinib; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010880:Piperidines / Q000494:pharmacology; D010997:Pleural Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000556:secondary; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011859:Radiography; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D015514:Oncogene Proteins, Fusion; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C415585:EML4 protein, human; D012697:Serine Endopeptidases; C582670:alectinib
keywords: Alectinib; bone metastasis; brain metastasis; crizotinib; pleural effusion