title: Novel irreversible EGFR tyrosine kinase inhibitor 324674 sensitizes human colon carcinoma HT29 and SW480 cells to apoptosis by blocking the EGFR pathway.
abstract: BACKGROUND
  Epidermal growth factor receptor (EGFR) is widely expressed in multiple solid tumors including colorectal cancer by promoting cancer cell growth and proliferation. Therefore, the inhibition of EGFR activity may establish a clinical strategy of cancer therapy.
  
  
  METHODS
  In this study, using human colon adenocarcinoma HT29 and SW480 cells as research models, we compared the efficacy of four EGFR inhibitors in of EGFR-mediated pathways, including the novel irreversible inhibitor 324674, conventional reversible inhibitor AG1478, dual EGFR/HER2 inhibitor GW583340 and the pan-EGFR/ErbB2/ErbB4 inhibitor. Cell proliferation was assessed by MTT analysis, and apoptosis was evaluated by the Annexin-V binding assay. EGFR and its downstream signaling effectors were examined by western blotting analysis.
  
  
  RESULTS
  Among the four inhibitors, the irreversible EGFR inhibitor 324674 was more potent at inhibiting HT29 and SW480 cell proliferation and was able to efficiently induce apoptosis at lower concentrations. Western blotting analysis revealed that AG1478, GW583340 and pan-EGFR/ErbB2/ErbB4 inhibitors failed to suppress EGFR activation as well as the downstream mitogen-activated protein kinase (MAPK) and PI3K/AKT/mTOR (AKT) pathways. In contrast, 324674 inhibited EGFR activation and the downstream AKT signaling pathway in a dose-dependent manner.
  
  
  CONCLUSIONS
  Our studies indicated that the novel irreversible EGFR inhibitor 324674 may have a therapeutic application in colon cancer therapy.
authors.affiliation: Division of Colorectal Surgery, Third Affiliated Hospital of Harbin Medical University, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Yu
authors.forename: Binbin
authors.initials: B
authors.lastname: Cui
authors.forename: Yinghu
authors.initials: Y
authors.lastname: Jin
authors.forename: Haipeng
authors.initials: H
authors.lastname: Chen
authors.forename: Xishan
authors.initials: X
authors.lastname: Wang
mesh_terms: D000813:Anilides / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002277:Carcinoma / Q000201:enzymology*; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D019073:HT29 Cells; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines; D020032:Tyrphostins / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000813:Anilides; C561722:EGFR tyrosine kinase inhibitor 324674; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; C512478:EGFR protein, human; D066246:ErbB Receptors