title: Targeting EGFR and PI3K pathways in ovarian cancer.
abstract: BACKGROUND
  The epidermal growth factor receptor (EGFR) is expressed in ovarian cancer, but agents targeting this pathway have shown little effect as single agents. This may be due to the presence of alternative pathways, particularly activation of the PI3K/Akt/MTOR pathway.
  
  
  METHODS
  We have therefore examined the effect of inhibitors of this pathway (ZSTK474 and sirolimus) in combination with the EGFR inhibitors erlotinib and gefitinib in ovarian cancer primary cell cultures.
  
  
  RESULTS
  The single-agent EGFR inhibitors showed little activity, although some activity was seen with the single-agent PI3K inhibitor, ZSTK474. Combinations of ZSTK474 with EGFR inhibitors showed enhanced activity with some evidence of synergy, whereas sirolimus combinations were less active. The results were not explicable on the basis of PIK3CA mutation or amplification, or PTEN loss, although one tumour with a KRAS mutation showed resistance to EGFR inhibitors. However, there was correlation of the EGFR expression with sensitivity to EGFR and resistance to PI3K active agents, and inverse correlation in the sensitivity of individual tumours to agents active against these pathways, suggesting a mechanism of action for the combination.
  
  
  CONCLUSIONS
  Phase I/II clinical trials with these agents should include further pharmacodynamic endpoints and molecular characterisation to identify patients most likely to benefit from this strategy.
authors.affiliation: Translational Oncology Research Centre, Queen Alexandra Hospital, Portsmouth PO6 3LY, UK.
authors.forename: S
authors.initials: S
authors.lastname: Glaysher
authors.forename: L M
authors.initials: LM
authors.lastname: Bolton
authors.forename: P
authors.initials: P
authors.lastname: Johnson
authors.forename: N
authors.initials: N
authors.lastname: Atkey
authors.forename: M
authors.initials: M
authors.lastname: Dyson
authors.forename: C
authors.initials: C
authors.lastname: Torrance
authors.forename: I A
authors.initials: IA
authors.lastname: Cree
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D020123:Sirolimus; D014227:Triazines; C510150:ZSTK474; C512478:EGFR protein, human
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