AZD6244 (ARRY-142886) enhances the therapeutic efficacy of sorafenib in mouse models of gastric cancer.
Gastric cancer is a deadly disease for which current therapeutic options are extremely limited. Vascular endothelial growth factor receptors and platelet-derived growth factor receptors regulate gastric cancer cell proliferation, invasion, and tumor angiogenesis. In the present study, we report that sorafenib therapy effectively inhibited tumor growth and angiogenesis in tumor xenografts. These were associated with reduction in the phosphorylation of vascular endothelial growth factor receptor-2 Tyr951, c-Kit Tyr568/570, platelet-derived growth factor receptor-beta Tyr1021, and Akt Ser473 and Thr308, down-regulation of positive cell cycle regulators, increased apoptosis, and up-regulation of p27. Sorafenib treatment also caused up-regulation of p-c-Raf Ser338 and p-extracellular signal-regulated kinase (ERK) Thr202/Tyr204 in gastric cancer xenografts. The combination of sorafenib and MAP/ERK kinase inhibitor AZD6244 enhances the effectiveness of each compound alone. Potential effect of sorafenib/AZD6244 included increase in proapoptotic Bim. Our data show that MAP/ERK kinase inhibition enhances the antitumor activity of sorafenib in vivo, supporting a rationale for multitargeted suppression of the angiogenesis and ERK signaling network in gastric cancer therapy.
Yang
Shu
S
Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre of Singapore, Singapore 169610.
Ngo
Van Chanh
VC
Lew
Guo Bin
GB
Chong
Lih Wen Valerie
LW
Lee
Swee Shean
SS
Ong
Wei Jie Richard
WJ
Lam
Wei Ling Irene
WL
Thng
Choon Hua
CH
Koong
Heng Nung
HN
Ong
Hock Soo
HS
Chung
Alexander
A
Chow
Pierce
P
Lee
Jonathan
J
Soo
Khee Chee
KC
Huynh
Hung
H
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000627:therapeutic use*; D000077157:Sorafenib; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology
C517975:AZD 6244; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D001562:Benzimidazoles; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib