title: ZD6474 induces growth arrest and apoptosis of GIST-T1 cells, which is enhanced by concomitant use of sunitinib.
abstract: ZD6474 (Zactima, AstraZeneca, Macclesfield, UK) is an orally available, small-molecule inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinases, with additional activity versus rearranged during transfection (RET). This study explored the effect of ZD6474 in gastrointestinal stromal tumor-T1 (GIST-T1) cells that possess a gain of function mutation in exon 11 of the c-KIT gene. ZD6474 induced growth arrest and apoptosis of GIST-T1 cells in association with blockade of c-Kit and its downstream effectors, including Akt and extracellular signal-regulated kinase (ERK). ZD6474 treatment also blocked the mammalian target of rapamycin (mTOR), which lies downstream of Akt and ERK. Interestingly, when ZD6474 was combined with sunitinib (SU11248; Sutent, Pfizer, Kalamazoo, MI, USA), a class III and V receptor tyrosine kinase inhibitor, the ZD6474-mediated growth inhibition was potentiated in association with further down-regulation of the mTOR targets p-p70S6K and p-4E-BP-1. The combination of ZD6474 and sunitinib should be investigated further.
authors.affiliation: Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100083, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ikezoe
authors.forename: Chie
authors.initials: C
authors.lastname: Nishioka
authors.forename: Takahiro
authors.initials: T
authors.lastname: Taguchi
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Zhu
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
authors.forename: Hirokuni
authors.initials: H
authors.lastname: Taguchi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects*; D004359:Drug Therapy, Combination; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011758:Pyrroles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000077210:Sunitinib; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D007211:Indoles; D010750:Phosphoproteins; D010880:Piperidines; D011758:Pyrroles; D011799:Quinazolines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000077210:Sunitinib; C452423:vandetanib