title: Inducible EGFR T790M-mediated gefitinib resistance in non-small cell lung cancer cells does not modulate sensitivity to PI103 provoked autophagy.
abstract: BACKGROUND
  Non-small cell lung cancer (NSCLC) with certain activating mutations in the epidermal growth factor receptor (EGFR) is sensitive to the small molecule EGFR tyrosine kinase inhibitors gefitinib and erlotinib, although acquired resistance eventually develops. Resistance is often mediated by acquisition of the T790M mutation in the activated EGFR allele. The aim of this study was to investigate in an EGFR tyrosine kinase inhibitor sensitive NSCLC cell line model, the impact of induced EGFR T790M expression on the cell biology and sensitivity to novel therapeutic strategies.
  
  
  METHODS
  Doxycycline inducible EGFR T790M-mediated drug resistance was generated in the clinically relevant HCC827 NSCLC cell line. Cell fate, the activities of EGFR and downstream signaling molecules, and the sensitivity to downstream inhibition of EGFR signaling networks were examined in the presence or absence of induced EGFR T790M expression.
  
  
  RESULTS
  Inducible EGFR T790M expression generated acquired resistance to EGFR inhibitors in HCC827 cells as expected. However, induced EGFR T790M expression did not affect activity of EGFR downstream signaling pathways or cell proliferation under the conditions tested. Moreover, sensitivity to inhibition of signaling molecules downstream of EGFR was unaffected by induced EGFR T790M. Importantly, HCC827 cells remained sensitive to class I phosphatidyl-inositol-3-kinase and mammalian target of rapamycin inhibition, which provoked pronounced autophagy, without significant apoptosis.
  
  
  CONCLUSIONS
  Phosphatidyl-inositol-3-kinase /mammalian target of rapamycin inhibition is a potentially effective therapeutic strategy against NSCLC with acquired resistance to EGFR inhibition. However, the implications of drug-induced autophagy in NSCLC need further exploration.
authors.affiliation: Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom.
authors.forename: Flavia F
authors.initials: FF
authors.lastname: Moreira-Leite
authors.forename: Luke R
authors.initials: LR
authors.lastname: Harrison
authors.forename: Alexandr
authors.initials: A
authors.lastname: Mironov
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Roberts
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005663:Furans / Q000494:pharmacology*; D000077156:Gefitinib; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D047908:Intracellular Signaling Peptides and Proteins; C522973:PI103; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011799:Quinazolines; C546842:MTOR protein, human; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000077156:Gefitinib