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Updated: Mar 31, 2026
Isolation and Characterization of a Head and Neck Squamous Cell Carcinoma Subpopulation Having Stem Cell Characteristics
Published on: May 11, 2016
Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells
Se Jin Oh1,2, Kyung Hee Noh1,2, Young-Ho Lee1,2
1Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, 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.
Insights
Targeting cancer stemness with rapamycin synergizes with crizotinib to combat anaplastic lymphoma kinase (ALK)-positive non-small cell lung carcinoma (NSCLC), including crizotinib-resistant tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Anaplastic lymphoma kinase (ALK) fusions, like EML4-ALK, drive a subset of non-small cell lung carcinoma (NSCLC).
- Crizotinib effectively targets EML4-ALK but resistance develops through mutations or bypass pathways.
- Cancer stem cell (CSC) theory offers a potential explanation for tumorigenesis and drug resistance in NSCLC.
Purpose of the Study:
- To investigate the link between EML4-ALK-driven tumorigenesis and stem-like properties in NSCLC.
- To determine if targeting stemness can overcome crizotinib resistance in EML4-ALK+ NSCLC.
- To evaluate the therapeutic potential of combining CSC-targeting agents with crizotinib.
Main Methods:
- Assessed stem-like properties in EML4-ALK+ NSCLC cells.
- Treated cells with rapamycin, a CSC-targeting agent.
- Evaluated the synergistic anti-tumor effects of combined rapamycin and crizotinib treatment.
Main Results:
- Confirmed that stem-like properties in EML4-ALK+ NSCLC cells are dependent on ALK activity.
- Rapamycin treatment attenuated stem-like phenotypes, tumor formation, and stemness marker expression (ALDH, NANOG, OCT4).
- Combined rapamycin and crizotinib demonstrated synergistic anti-tumor effects on both crizotinib-sensitive and resistant EML4-ALK+ NSCLC cells.
Conclusions:
- Stemness is a critical driver in EML4-ALK+ NSCLC, contributing to tumorigenesis and resistance.
- Targeting cancer stemness with agents like rapamycin is a promising strategy.
- Combination therapy of rapamycin and crizotinib offers a novel approach to control intractable EML4-ALK+ NSCLC.
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