Cancer stem cell biomarkers in egfr-mutation–positive non–small-cell lung cancer
Abstract
Introduction Epidermal growth factor receptor (EGFR) pathway deregulation promotes the acquisition of stemlike properties in non-small-cell lung cancer. EGFR inhibition through NOTCH enriches lung cancer stem cells (CSCs). Src through Yes-associated protein 1 (YAP1) activates NOTCH. Signal transduction and activator of transcription 3 (STAT3) activation occurs upon EGFR blockade and regulates the generation of CSCs.Patients and methods Using the Aldefluor assay kit, we investigated the enrichment of aldehyde dehydrogenase (ALDH)-positive cells in EGFR-mutation-positive cells treated with gefitinib, afatinib, and osimertinib. Western blot analysis was performed to evaluate changes in CSC marker expression upon EGFR blockade. We performed gene expression analysis in a cohort of EGFR-mutation-positive non-small-cell lung cancer patients. We evaluated the association of gene expression with treatment outcomes.Results The cell subpopulation surviving EGFR inhibition had high ALDH activity and elevated CSC marker expression. Concurrent inhibition of EGFR, STAT3, and Src diminished the CSC subpopulation in an EGFR-mutation-positive cellular model. In a cohort of 64 EGFR-mutation-positive patients, 2 ALDH1 isoforms and the NOTCH target hairy and enhancer of split 1 (HES1), when highly expressed, were predictive of worse outcome to EGFR blockade. The gene expression of B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) that maintains the self-renewal of stem cells was also related to treatment outcome.Conclusion Single EGFR inhibitors increase the population of CSCs. Combinatory therapy targeting STAT3 and Src may be of potential benefit. ALDH1, HES1, and Bmi-1 are essential biomarkers in the initial assessment of EGFR-mutation-positive patients.
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For lung cancer, ALDH, CD44, Oct4, c-kit, and Nestin are among the most frequently observed CSCs markers that promote tumor development.
“For lung cancer, ALDH, CD44, Oct4, c-kit, and Nestin were shown to be some of the most frequently observed CSCs markers which promote tumor development [53,54,85,86,87].”
From 20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells (2023) · cites this paper as [87]
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- Authors
- Codony-Servat, J., Codony-Servat, C., Cardona, A. F., Giménez-Capitán, A., Drozdowskyj, A., Berenguer, J., Bracht, J. W. P., Ito, M., Karachaliou, N., & Rosell, R.
- Affiliations
- Foundation for Clinical and Applied Cancer Research (CO)
- Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES)
- Hiroshima University (JP)
- Instituto Oncológico Dr. Rosell (ES)
- Corresponding author
- Rosell, Rafael
- ORCID
- Venue
- Clinical Lung Cancer
- Publisher
- Elsevier BV
- Published
- 2019-05
- Volume
- 20
- Issue
- 3
- Pages
- 167-177
- ISSN
- 1525-7304 (ISSN-L)
- OpenAlex
- W2918097509
- Cited by
- 46
- References
- 32
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 12 · 2020: 8 · 2019: 4
- FWCI
- 5.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Lung Cancer (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Center for Outcomes Research and Evaluation, Yale School of Medicine
- “la Caixa” Foundation
- Fundación Científica Asociación Española Contra el Cáncer (PROYE18012ROSE)
- Instituto de Salud Carlos III (ELBA 765492, PIE16/00011)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- cancer stem cells, EGFR mutation, non-small cell lung cancer, EGFR inhibitors, gefitinib, afatinib, osimertinib, aldehyde dehydrogenase, ALDH1, STAT3, Src kinase, YAP, Notch signaling, Hes1, BMI1, predictive biomarkers, combination therapy
- MeSH terms
- Transcription Factor HES-1, Aldehyde Dehydrogenase 1 Family, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Drug Therapy, Combination, Humans, Lung Neoplasms, Mutation, Biomarkers, Tumor, Neoplastic Stem Cells, Gene Expression Regulation, Neoplastic, src-Family Kinases, Cell Line, Tumor, Protein Kinase Inhibitors, STAT3 Transcription Factor, Polycomb Repressive Complex 1, ErbB Receptors
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