AZD6244 (ARRY-142886) enhances the therapeutic efficacy of sorafenib in mouse models of gastric cancer

被引：30

作者：

Yang, Shu ^{[1
]}

Ngo, Van Chanh ^{[1
]}

Bin Lew, Guo ^{[1
]}

Chong, Lih Wen Valerie ^{[1
]}

Lee, Swee Shean ^{[1
]}

Ong, Wei Jie Richard ^{[1
]}

Lam, Wei Ling Irene ^{[1
]}

Thng, Choon Hua ^{[2
]}

Koong, Heng Nung ^{[3
]}

Ong, Hock Soo ^{[4
]}

Chung, Alexander ^{[4
]}

Chow, Pierce ^{[4
]}

Lee, Jonathan ^{[5
]}

Soo, Khee Chee ^{[1
]}

Huynh, Hung ^{[1
]}

机构：

[1] Natl Canc Ctr, Mol Endocrinol Lab, Div Cellular & Mol Res, Humphrey Oei Inst Canc Res, Singapore 169610, Singapore

[2] Natl Canc Ctr, Humphrey Oei Inst Canc Res, Dept Oncol Imaging, Singapore 169610, Singapore

[3] Natl Canc Ctr, Humphrey Oei Inst Canc Res, Dept Med Oncol, Singapore 169610, Singapore

[4] Singapore Gen Hosp, Dept Gen Surg, Singapore 0316, Singapore

[5] Univ New S Wales, Fac Med, Sydney, NSW, Australia

来源：

MOLECULAR CANCER THERAPEUTICS | 2009年 / 8卷 / 09期

关键词：

ENDOTHELIAL-GROWTH-FACTOR; RECEPTOR TYROSINE KINASES; HEPATOCELLULAR-CARCINOMA; RAF/MEK/ERK PATHWAY; FACTOR EXPRESSION; ANGIOGENESIS; INHIBITION; ACTIVATION; MAPK; RAF;

D O I：

10.1158/1535-7163.MCT-09-0213

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 anti-tumor activity of sorafenib in vivo, supporting a rationale for multitargeted suppression of the angiogenesis and ERK signaling network in gastric cancer therapy. [Mol Cancer Ther 2009;8(9):2537-45]

引用

页码：2537 / 2545

页数：9

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