Antagonistic and agonistic effects of quinazoline tyrosine kinase inhibitors on mutant EGF receptor function.
A mutated form of the EGF receptor (EGFRvIII), resulting from deletion of exons 2-7, is an oncogenic protein that is expressed in multiple human tumors. This mutation induces ligand-independent activation of the EGFR tyrosine kinase and thereby can initiate unregulated cell growth and tumorigenesis. Thus, inhibition of the kinase activity of EGFRvIII is a potential means of suppressing its oncogenic properties. Certain tyrosine kinase inhibitors (tyrphostins) specifically inhibit the wild-type EGFR and thereby inhibit tumor growth both in vitro and in vivo. We demonstrate that the quinazoline tyrphostins AG 1478 and AG 1517 can suppress morphologic transformation of cell lines by EGFRvIII. Quinazolines were found to inhibit receptor autophosphorylation and signaling through MAP kinase, but had minimal effects on association of EGFRvIII with Grb2/SOS. Low concentrations of quinazoline also increased receptor dimerization and phosphotyrosine content. This was associated with increases in colony formation in soft agar and increased invasion through matrigel for AG 1478. Thus, both AG 1478 and AG 1517 can inhibit multiple EGFRvIII signaling pathways, but at low concentrations AG 1478 can enhance colony formation, presumably related to augmented homodimerization of the receptor and activation of downstream signaling.
Montgomery
R Bruce
RB
Department of Medicine, Division of Oncology, University of Washington and VA Puget Sound HCS, Seattle, WA 98108, USA. rbmontgo@u.washington.edu
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D048429:Cell Size / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D019281:Dimerization; D066246:ErbB Receptors / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000235:genetics; D051380:GRB2 Adaptor Protein; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D020032:Tyrphostins / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D011506:Proteins; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases