Open AccessZD6474 induces growth arrest and apoptosis of GIST‐T1 cells, which is enhanced by concomitant use of sunitinib
Author(s) -
Yang Yang,
Ikezoe Takayuki,
Nishioka Chie,
Taguchi Takahiro,
Zhu Weiguo,
Koeffler H. Phillip,
Taguchi Hirokuni
Publication year - 2006
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2006.00325.x
Subject(s) - apoptosis , concomitant , sunitinib , cancer research , gist , chemistry , medicine , microbiology and biotechnology , biology , biochemistry , stromal cell , cancer
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. ( Cancer Sci 2006; 97: 1404–1409)