title: Activity of EGFR, mTOR and PI3K inhibitors in an isogenic breast cell line model.
abstract: BACKGROUND
  The epidermal growth factor receptor family is expressed in breast cancer, and agents targeting this pathway have single agent effects (e.g. traztuzumab). Development of resistance may be due to the presence of alternative pathways, particularly activation of the PI3K/Akt/MTOR pathway. We have therefore examined the effect of inhibitors of this pathway (ZSTK474 and sirolimus) in combination with the epidermal growth factor (EGFR) inhibitors erlotinib and gefitinib in breast MCF10a isogenic cell lines with EGFR, BRAF, AKT, and PI3K mutations.
  
  
  RESULTS
  PI3K mutation conferred increased activity of EGFR inhibitors against MCF10a cells in comparison with the parental cell line and other mutations studied. Combination of EGFR inhibitors with either the PI3K inhibitor ZSTK474 or the MTOR inhibitor sirolimus showed increased activity.
  
  
  CONCLUSIONS
  These results are encouraging for the use of combinations targeting the PI3K and EGFR pathway simultaneously.
authors: Sharon
authors: S
authors: Glaysher
authors: Louise M
authors: LM
authors: Bolton
authors: Penny
authors: P
authors: Johnson
authors: Christopher
authors: C
authors: Torrance
authors: Department of Pathology, University Hospitals Coventry and Warwickshire, Coventry, UK. i.a.cree@warwick.ac.uk.
authors: Ian A
authors: IA
authors: Cree
mesh_terms: D001940:Breast / Q000166:cytology / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D006801:Humans; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014227:Triazines; C510150:ZSTK474; C546842:MTOR protein, human