title: Properties of resistant cells generated from lung cancer cell lines treated with EGFR inhibitors.
abstract: BACKGROUND
  Epidermal growth factor receptor (EGFR) signaling plays an important role in non-small cell lung cancer (NSCLC) and therapeutics targeted against EGFR have been effective in treating a subset of patients bearing somatic EFGR mutations. However, the cancer eventually progresses during treatment with EGFR inhibitors, even in the patients who respond to these drugs initially. Recent studies have identified that the acquisition of resistance in approximately 50% of cases is due to generation of a secondary mutation (T790M) in the EGFR kinase domain. In about 20% of the cases, resistance is associated with the amplification of MET kinase. In the remaining 30-40% of the cases, the mechanism underpinning the therapeutic resistance is unknown.
  
  
  METHODS
  An erlotinib resistant subline (H1650-ER1) was generated upon continuous exposure of NSCLC cell line NCI-H1650 to erlotinib. Cancer stem cell like traits including expression of stem cell markers, enhanced ability to self-renew and differentiate, and increased tumorigenicity in vitro were assessed in erlotinib resistant H1650-ER1 cells.
  
  
  RESULTS
  The erlotinib resistant subline contained a population of cells with properties similar to cancer stem cells. These cells were found to be less sensitive towards erlotinib treatment as measured by cell proliferation and generation of tumor spheres in the presence of erlotinib.
  
  
  CONCLUSIONS
  Our findings suggest that in cases of NSCLC accompanied by mutant EGFR, treatment targeting inhibition of EGFR kinase activity in differentiated cancer cells may generate a population of cancer cells with stem cell properties.
authors.affiliation: Department of Chemical and Biological Engineering, University of Wisconsin, Madison, 53706, USA.
authors.forename: Gargi
authors.initials: G
authors.lastname: Ghosh
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Lian
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kron
authors.forename: Sean P
authors.initials: SP
authors.lastname: Palecek
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay / Q000379:methods
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors