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

Se Jin Oh, Kyung Hee Noh, Young Ho Lee, Soon Oh Hong, Kwon Ho Song, Hyo Jung Lee, Soyeon Kim, Tae Min Kim, Ju Hong Jeon, Jae Hong Seo, Dong Wan Kim, Tae Woo Kim

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 stemlike 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.

Original languageEnglish
Pages (from-to)40255-40267
Number of pages13
JournalOncotarget
Volume6
Issue number37
DOIs
Publication statusPublished - 2015

Keywords

  • EML4-ALK
  • NSCLC
  • Rapamycin
  • Resistance
  • Stemness factor

ASJC Scopus subject areas

  • Oncology

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    Oh, S. J., Noh, K. H., Lee, Y. H., Hong, S. O., Song, K. H., Lee, H. J., Kim, S., Kim, T. M., Jeon, J. H., Seo, J. H., Kim, D. W., & Kim, T. W. (2015). Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells. Oncotarget, 6(37), 40255-40267. https://doi.org/10.18632/oncotarget.5434