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

Authors
Oh, Se JinNoh, Kyung HeeLee, Young-HoHong, Soon-OhSong, Kwon-HoLee, Hyo-JungKim, SoyeonKim, Tae MinJeon, Ju-HongSeo, Jae HongKim, Dong-WanKim, Tae Woo
Issue Date
24-11월-2015
Publisher
IMPACT JOURNALS LLC
Keywords
EML4-ALK; stemness factor; rapamycin; resistance; NSCLC
Citation
ONCOTARGET, v.6, no.37, pp.40255 - 40267
Indexed
SCIE
SCOPUS
Journal Title
ONCOTARGET
Volume
6
Number
37
Start Page
40255
End Page
40267
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/91872
DOI
10.18632/oncotarget.5434
ISSN
1949-2553
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.
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