title: CD133-Positive Cells from Non-Small Cell Lung Cancer Show Distinct Sensitivity to Cisplatin and Afatinib.
abstract: The standard of care for advanced non-small cell lung cancer (NSCLC) consists in cisplatin-combination chemotherapy. In patients bearing tumors with activating mutations of the epidermal growth factor receptor (EGFR), the inhibition of the EGFR intracellular tyrosine kinase can induce up to 80 % response rates. However, both therapeutic strategies will eventually lead to recurrent disease due to the development of drug resistance. The identification of rare cancer stem-like cells able to repopulate the tumor, after failure to standard treatment modalities, has led to characterize these cells as potential therapeutic targets. This article will address the role of the CD133/EpCAM stem cell-related markers and explore cell sensitivity to cisplatin and to the EGFR-tyrosine kinase inhibitor, afatinib. Three human NSCLC cell lines, one wild-type (A549) and two harboring EGFR mutations (H1650 and H1975), as well as 20 NSCLC primary cultures, were grown in non-differentiating culture conditions for stem cell enrichment. Flow-cytometry analyses of CD133 and EpCAM and cell sensitivity to cisplatin and afatinib were performed. Moreover, the expression of activated EGFR was assessed by Western blot. The cell lines and primary cultures grown in non-differentiating culture conditions were enriched with CD133/EpCAM-positive cells and were significantly more resistant to cisplatin and more sensitive to afatinib as compared to the differentiated counterpart. In addition, increased EGFR-phosphorylation in non-differentiated cultures was observed. The present findings suggest that afatinib might be beneficial for patients bearing tumors with constitutively activated EGFR, to target chemo-resistant CD133/EpCAM-positive cancer stem cells.
authors: Lung Cancer Unit, IRCCS A.O.U. San Martino-IST, National Institute for Cancer Research, Largo Rosanna Benzi, 10, 16132, Genoa, Italy, angela.alama@hsanmartino.it.
authors: Angela
authors: A
authors: Alama
authors: Rosaria
authors: R
authors: Gangemi
authors: Silvano
authors: S
authors: Ferrini
authors: Gaia
authors: G
authors: Barisione
authors: Anna Maria
authors: AM
authors: Orengo
authors: Mauro
authors: M
authors: Truini
authors: Maria Giovanna Dal
authors: MG
authors: Bello
authors: Francesco
authors: F
authors: Grossi
mesh_terms: D000071916:AC133 Antigen; D000077716:Afatinib; D015703:Antigens, CD / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004359:Drug Therapy, Combination; D000071858:Epithelial Cell Adhesion Molecule; D066246:ErbB Receptors / Q000235:genetics; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000502:physiology; D010455:Peptides / Q000378:metabolism; D011799:Quinazolines / Q000627:therapeutic use*
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; D011799:Quinazolines; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin