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

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-A...

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Main Authors:	Oh, Se Jin, Noh, Kyung Hee, Lee, Young-Ho, Hong, Soon-Oh, Song, Kwon-Ho, Lee, Hyo-Jung, Kim, Soyeon, Kim, Tae Min, Jeon, Ju-Hong, Seo, Jae Hong, Kim, Dong-Wan, Kim, Tae Woo
Format:	Online
Language:	English
Published:	Impact Journals LLC 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741893/

id	pubmed-4741893
recordtype	oai_dc
spelling	pubmed-47418932016-03-23 Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells Oh, Se Jin Noh, Kyung Hee Lee, Young-Ho Hong, Soon-Oh Song, Kwon-Ho Lee, Hyo-Jung Kim, Soyeon Kim, Tae Min Jeon, Ju-Hong Seo, Jae Hong Kim, Dong-Wan Kim, Tae Woo Research Paper 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. Impact Journals LLC 2015-10-22 /pmc/articles/PMC4741893/ /pubmed/26517679 Text en Copyright: © 2015 Oh et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Oh, Se Jin Noh, Kyung Hee Lee, Young-Ho Hong, Soon-Oh Song, Kwon-Ho Lee, Hyo-Jung Kim, Soyeon Kim, Tae Min Jeon, Ju-Hong Seo, Jae Hong Kim, Dong-Wan Kim, Tae Woo
spellingShingle	Oh, Se Jin Noh, Kyung Hee Lee, Young-Ho Hong, Soon-Oh Song, Kwon-Ho Lee, Hyo-Jung Kim, Soyeon Kim, Tae Min Jeon, Ju-Hong Seo, Jae Hong Kim, Dong-Wan Kim, Tae Woo Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells
author_facet	Oh, Se Jin Noh, Kyung Hee Lee, Young-Ho Hong, Soon-Oh Song, Kwon-Ho Lee, Hyo-Jung Kim, Soyeon Kim, Tae Min Jeon, Ju-Hong Seo, Jae Hong Kim, Dong-Wan Kim, Tae Woo
author_sort	Oh, Se Jin
title	Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells
title_short	Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells
title_full	Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells
title_fullStr	Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells
title_full_unstemmed	Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells
title_sort	targeting stemness is an effective strategy to control eml4-alk+ non-small cell lung cancer cells
description	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.
publisher	Impact Journals LLC
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741893/
_version_	1613533983154372608

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

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