title: AZD6244 (ARRY-142886) enhances the therapeutic efficacy of sorafenib in mouse models of gastric cancer.
abstract: 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.
authors.affiliation: Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre of Singapore, Singapore 169610.
authors.forename: Shu
authors.initials: S
authors.lastname: Yang
authors.forename: Van Chanh
authors.initials: VC
authors.lastname: Ngo
authors.forename: Guo Bin
authors.initials: GB
authors.lastname: Lew
authors.forename: Lih Wen Valerie
authors.initials: LW
authors.lastname: Chong
authors.forename: Swee Shean
authors.initials: SS
authors.lastname: Lee
authors.forename: Wei Jie Richard
authors.initials: WJ
authors.lastname: Ong
authors.forename: Wei Ling Irene
authors.initials: WL
authors.lastname: Lam
authors.forename: Choon Hua
authors.initials: CH
authors.lastname: Thng
authors.forename: Heng Nung
authors.initials: HN
authors.lastname: Koong
authors.forename: Hock Soo
authors.initials: HS
authors.lastname: Ong
authors.forename: Alexander
authors.initials: A
authors.lastname: Chung
authors.forename: Pierce
authors.initials: P
authors.lastname: Chow
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lee
authors.forename: Khee Chee
authors.initials: KC
authors.lastname: Soo
authors.forename: Hung
authors.initials: H
authors.lastname: Huynh
mesh_terms: 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
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D001562:Benzimidazoles; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib