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- Title
Cancer Stem Cell Biomarkers in EGFR-Mutation-Positive Non-Small-Cell Lung Cancer.
- Authors
Codony-Servat, Jordi; Codony-Servat, Carles; Cardona, Andrés Felipe; Giménez-Capitán, Ana; Drozdowskyj, Ana; Berenguer, Jordi; Bracht, Jillian Wilhelmina Paulina; Ito, Masaoki; Karachaliou, Niki; Rosell, Rafael
- Abstract
<bold>Introduction: </bold>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.<bold>Patients and Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>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.
- Publication
Clinical Lung Cancer, 2019, Vol 20, Issue 3, p167
- ISSN
1525-7304
- Publication type
journal article
- DOI
10.1016/j.cllc.2019.02.005