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  • br Jordi Codony Servat Carles Codony Servat Andr s


    Jordi Codony-Servat,1 Carles Codony-Servat,1 Andrés Felipe Cardona,3,4 Ana Giménez-Capitán,1 Ana Drozdowskyj,5 Jordi Berenguer,1 Jillian Wilhelmina Paulina Bracht,1 Masaoki Ito,1,7 Niki Karachaliou,1,8 Rafael Rosell1,2,5,6
    Epidermal growth factor receptor (EGFR) signaling deregulation promotes cancer stem cell (CSC) enrichment in nonesmall-cell lung cancer (NSCLC). In vitro experiments showed that inhibition of EGFR, signal transducer and activator of transcription 3 (STAT3), and Src decreased the CSC subpopulation. High expression of aldehyde de-hydrogenase (ALDH) 1 isoforms and target hairy and enhancer of split 1 (HES1) was predictive of worse outcome to EGFR inhibition in EGFR-mutationepositive NSCLC patients. ALDH1, HES1, and B-cellespecific Moloney murine leukemia virus integration site 1 (Bmi-1) could be useful as biomarkers to monitor clinical progression, and the use of STAT3 and Src inhibitors could be useful to inhibit the CSC subpopulation induced by EGFR inhibitor treatment. Introduction: Epidermal growth factor receptor (EGFR) pathway deregulation promotes the acquisition of stemlike properties in nonesmall-cell lung cancer. EGFR inhibition through NOTCH enriches lung cancer stem Ursodiol (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-mutationepositive 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-mutationepositive nonesmall-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-mutationepositive cellular model. In a cohort of 64 EGFR-mutationepositive 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-cellespecific Moloney murine leukemia virus inte-gration 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-mutationepositive patients.
    Keywords: ALDH, Bmi-1, HES1, NSCLC, Resistance
    The J.C.-S. and R.R. authors are the senior authors.
    1Pangaea Oncology, Laboratory of Molecular Biology 2Instituto Oncológico Dr Rosell (IOR), Quirón-Dexeus University Institute, Barcelona, Spain
    3Clinical and Translational Oncology Group, Thoracic Oncology Unit, Institute of Oncology, Clínica del Country, Bogotá, Colombia 4Foundation for Clinical and Applied Cancer Research (FICMAC), Bogotá, Colombia 5Institut d’Investigació en Ciències Germans Trias i Pujol 6Institut Català d’Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain 7Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
    8Instituto Oncológico Dr Rosell (IOR), University Hospital Sagrat Cor, Quiron Salud Group Barcelona, Barcelona, Spain
    Address for correspondence: Jordi Codony-Servat, PhD and Rafael Rosell, MD, PhD,
    Pangaea Oncology, Laboratory of Molecular Biology, Quirón-Dexeus University Institute, Barcelona, Spain E-mail contact: [email protected]; [email protected]
    Cancer Stem Cell Biomarkers
    In several human cancers, cancer stem cells (CSCs) are highly rele-vant and are associated with tumor progression, genetic instability, and drug resistance.1 These cells possess self-renewal capacity and are involved in tumor maintenance, metastases, and resistance to anti-tumor compounds,1-4 including targeted therapies. Aldehyde dehy-drogenase 1 (ALDH1), a detoxifying enzyme responsible for the oxidation of intracellular aldehydes, has been identified as a CSC marker in nonesmall-cell lung cancer (NSCLC)5 and is related to resistance to therapies.6 B-lymphoma Moloney murine leukemia virus insertion region 1 (Bmi-1), a well-known epithelialemesenchymal transition (EMT)-inducing transcription factor, is also involved in the maintenance of CSCs.7 Moreover, the NOTCH signaling pathway is essential for the tumorigenicity of CSCs.8 We have shown that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) induce the activation of signal transducer and activator of transcription 3 (STAT3) in EGFR-mutationepositive cells.9,10 The EGFR TKI afatinib induced STAT3 activation and increased the ALDHþ cell population in the EGFR-mutationepositive PC9 cell line.10 Still, when we combined afatinib with a STAT3 inhibitor in vitro, we were not able to avoid, either the enrichment in the ALDHþ subpopulation, or the increase of the expression of the NOTCH target hairy and enhancer of split 1 (HES1), events that occur upon single EGFR blockade.10 This is because, independent of STAT3, the interleukin-6 signaling pathway activates the Yes-associated protein 1 (YAP1), and then NOTCH, through direct11 association with the Src-family kinase Yes.12 Erlotinib induces elevated ALDH activity in EGFR-mutationepositive NSCLC cells by activation of the NOTCH3 signaling pathway.6