title: Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells.
abstract: The fusion between anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) is a causative factor in a unique subset of patients with non-small cell lung carcinoma (NSCLC). Although the inhibitor crizotinib, as it blocks the kinase activity of the resulting EML4-ALK fusion protein, displays remarkable initial responses, a fraction of NSCLC cases eventually become resistant to crizotinib by acquiring mutations in the ALK domain or activating bypass pathways via EGFR, KIT, or KRAS. Cancer stem cell (CSC) theory provides a plausible explanation for acquisition of tumorigenesis and resistance. However, the question as to whether EML4-ALK-driven tumorigenesis is linked with the stem-like property and whether the stemness is an effective target in controlling EML4-ALK+ NSCLC including crizotinib-resistant NSCLC cells has not been addressed. Here, we report that stem-like properties stem from ALK activity in EML4-ALK+ NSCLC cells. Notably, treatment with rapamycin, a CSC targeting agent, attenuates stem-like phenotypes of the EML4-ALK+ cells, which increased capability of tumor formation and higher expression of stemness-associated molecules such as ALDH, NANOG, and OCT4. Importantly, combinational treatment with rapamycin and crizotinib leads to synergistic anti-tumor effects on EML4-ALK+ NSCLC cells as well as on those resistant to crizotinib. Thus, we provide a proof of principle that targeting stemness would be a novel strategy to control intractable EML4-ALK+ NSCLC.
authors.affiliation: Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Korea.|Department of Biochemistry & Molecular Biology, College of Medicine, Korea University, Seoul, Korea.
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Oh
authors.affiliation: Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Korea.|Department of Biochemistry & Molecular Biology, College of Medicine, Korea University, Seoul, Korea.
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Noh
authors.affiliation: Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Korea.|Department of Biochemistry & Molecular Biology, College of Medicine, Korea University, Seoul, Korea.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Korea.|Department of Biochemistry & Molecular Biology, College of Medicine, Korea University, Seoul, Korea.|Division of Oncology, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea.
authors.forename: Soon-Oh
authors.initials: SO
authors.lastname: Hong
authors.affiliation: Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Korea.|Department of Biochemistry & Molecular Biology, College of Medicine, Korea University, Seoul, Korea.
authors.forename: Kwon-Ho
authors.initials: KH
authors.lastname: Song
authors.affiliation: Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Korea.|Department of Biochemistry & Molecular Biology, College of Medicine, Korea University, Seoul, Korea.
authors.forename: Hyo-Jung
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Soyeon
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Tae Min
authors.initials: TM
authors.lastname: Kim
authors.affiliation: Department of Physiology, Seoul National University, College of Medicine, Seoul, Korea.
authors.forename: Ju-Hong
authors.initials: JH
authors.lastname: Jeon
authors.affiliation: Division of Oncology, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea.
authors.forename: Jae Hong
authors.initials: JH
authors.lastname: Seo
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Korea.|Department of Biochemistry & Molecular Biology, College of Medicine, Korea University, Seoul, Korea.
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000077547:Crizotinib; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D000067492:RNAi Therapeutics / Q000379:methods; D020123:Sirolimus / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000903:Antibiotics, Antineoplastic; C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D020123:Sirolimus
keywords: EML4-ALK; NSCLC; rapamycin; resistance; stemness factor