title: Response to dual blockade of epidermal growth factor receptor (EGFR) and cycloxygenase-2 in nonsmall cell lung cancer may be dependent on the EGFR mutational status of the tumor.
abstract: BACKGROUND
  Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated clinical benefit in patients with nonsmall cell lung cancer (NSCLC), particularly those with tumors that have EGFR-TK domain mutations. Moreover, the EGFR and cyclooxygenase (COX)-2 pathways are known to enhance the procarcinogenic effects of each other in different tumor types. Therefore, it was hypothesized that tumor EGFR mutation status may influence the effectiveness of simultaneous EGFR and COX-2 inhibition in patients with NSCLC.
  
  
  METHODS
  Three NSCLC cell lines with varying EGFR mutation status and sensitivities to EGFR-TKIs were selected: H3255 (L858R), H1650 (del E746-A750), and H1781 (wild-type EGFR). Cells were treated with erlotinib, gefitinib, or celecoxib alone, and the combination of both EGFR-TKI inhibitors with celecoxib. Cell survival and apoptosis was assessed and correlated with the expression of COX-2, EGFR, pEGFR, Akt, pAkt, expression, and derived prostaglandin E2 (PGE(2)).
  
  
  RESULTS
  Celecoxib by itself was found to have no effects on cell growth or apoptosis in any of the cell lines. Erlotinib and gefitinib inhibited cell growth and induced apoptosis in both mutant cell lines and did so in H1781 cells at 10-fold higher concentrations. Celecoxib when added to erlotinib or gefitinib significantly enhanced the antiproliferative and proapoptotic effects in both mutant cell lines but had no additional effects in H1781 cells. Greater down-regulation of COX-2, EGFR, pEGFR, Akt, pAkt, and PGE(2) was found when H3255 cells were treated with the combination compared with any of the single agents alone.
  
  
  CONCLUSIONS
  The results of the current study demonstrate that the effectiveness of the addition of celecoxib to an EGFR-TKI is significantly greater in NSCLC cells with EGFR mutations, which is likely due to more complete inhibition of both pathways.
authors.affiliation: Division of Hematology/Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA. gadgeels@karmanos.org
authors.forename: Shirish M
authors.initials: SM
authors.lastname: Gadgeel
authors.forename: Shadan
authors.initials: S
authors.lastname: Ali
authors.forename: Philip A
authors.initials: PA
authors.lastname: Philip
authors.forename: Fakhara
authors.initials: F
authors.lastname: Ahmed
authors.forename: Antoinette
authors.initials: A
authors.lastname: Wozniak
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism*; D000068579:Celecoxib; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D018773:Genes, erbB-1; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D011458:Prostaglandins E / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D011458:Prostaglandins E; D011720:Pyrazoles; D011799:Quinazolines; D013449:Sulfonamides; D000069347:Erlotinib Hydrochloride; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D066246:ErbB Receptors; D000068579:Celecoxib; D000077156:Gefitinib