title: Small tyrosine kinase inhibitors interrupt EGFR signaling by interacting with erbB3 and erbB4 in glioblastoma cell lines.
abstract: Signaling through the epidermal growth factor receptor (EGFR) is relevant in glioblastoma. We have determined the effects of the EGFR inhibitor AG1478 in glioblastoma cell lines and found that U87 and LN-229 cells were very sensitive to this drug, since their proliferation diminished and underwent a marked G(1) arrest. T98 cells were a little more refractory to growth inhibition and A172 cells did not undergo a G(1) arrest. This G(1) arrest was associated with up-regulation of p27(kip1), whose protein turnover was stabilized. EGFR autophosphorylation was blocked with AG1478 to the same extent in all the cell lines. Other small-molecule EGFR tyrosine kinase inhibitors employed in the clinic, such as gefitinib, erlotinib and lapatinib, were able to abrogate proliferation of glioblastoma cell lines, which underwent a G(1) arrest. However, the EGFR monoclonal antibody, cetuximab had no effect on cell proliferation and consistently, had no effect on cell cycle either. Similarly, cetuximab did not inhibit proliferation of U87 ΔEGFR cells or primary glioblastoma cell cultures, whereas small-molecule EGFR inhibitors did. Activity of downstream signaling molecules of EGFR such as Akt and especially ERK1/2 was interrupted with EGFR tyrosine kinase inhibitors, whereas cetuximab treatment could not sustain this blockade over time. Small-molecule EGFR inhibitors were able to prevent phosphorylation of erbB3 and erbB4, whereas cetuximab only hindered EGFR phosphorylation, suggesting that EGFR tyrosine kinase inhibitors may mediate their anti-proliferative effects through other erbB family members. We can conclude that small-molecule EGFR inhibitors may be a therapeutic approach for the treatment of glioblastoma patients.
authors: Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche (Alicante), Spain.
authors: Estefanía
authors: E
authors: Carrasco-García
authors: Miguel
authors: M
authors: Saceda
authors: Silvina
authors: S
authors: Grasso
authors: Lourdes
authors: L
authors: Rocamora-Reverte
authors: Mariano
authors: M
authors: Conde
authors: Angeles
authors: A
authors: Gómez-Martínez
authors: Pilar
authors: P
authors: García-Morales
authors: José A
authors: JA
authors: Ferragut
authors: Isabel
authors: I
authors: Martínez-Lacaci
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines; D012333:RNA, Messenger / Q000235:genetics; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D066247:Receptor, ErbB-4; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D020032:Tyrphostins; C101044:RTKI cpd; C512478:EGFR protein, human; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4