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Oncotarget. 2015 Nov 24;6(37):40255-67. doi: 10.18632/oncotarget.5434.

Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells.

Oh SJ1,2, Noh KH1,2, Lee YH1,2, Hong SO1,2,3, Song KH1,2, Lee HJ1,2, Kim S4, Kim TM4, Jeon JH5, Seo JH3, Kim DW4, Kim TW1,2.

Author information

1
Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Korea.
2
Department of Biochemistry & Molecular Biology, College of Medicine, Korea University, Seoul, Korea.
3
Division of Oncology, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea.
4
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
5
Department of Physiology, Seoul National University, College of Medicine, Seoul, Korea.

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.

KEYWORDS:

EML4-ALK; NSCLC; rapamycin; resistance; stemness factor

PMID:
26517679
PMCID:
PMC4741893
DOI:
10.18632/oncotarget.5434
[Indexed for MEDLINE]
Free PMC Article

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