Targeting mTOR network in colorectal cancer therapy

被引:83
作者
Wang, Xiao-Wen [1 ]
Zhang, Yan-Jie [1 ,2 ]
机构
[1] Rutgers Canc Inst New Jersey, New Brunswick, NJ 08903 USA
[2] Shanghai Jiao Tong Univ, Sch Med, Peoples Hosp 3, Dept Gastroenterol, Shanghai 201900, Peoples R China
关键词
Mechanistic target of rapamycin pathway; Colorectal cancer; Mechanistic target of rapamycin inhibitor; Chemotherapy; Drug resistance; ACTIVATED PROTEIN-KINASE; ABERRANT CRYPT FOCI; PHASE-II TRIAL; MAMMALIAN TARGET; SIGNALING PATHWAY; COLON-CANCER; BETA-CATENIN; TUBEROUS SCLEROSIS; RAG GTPASES; DIABETES-MELLITUS;
D O I
10.3748/wjg.v20.i15.4178
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
The mechanistic target of rapamycin (mTOR) integrates growth factor signals with cellular nutrient and energy levels and coordinates cell growth, proliferation and survival. A regulatory network with multiple feedback loops has evolved to ensure the ex-quisite regulation of cell growth and division. Colorectal cancer is the most intensively studied cancer because of its high incidence and mortality rate. Multiple genetic alterations are involved in colorectal carcinogenesis, including oncogenic Ras activation, phosphatidylinositol 3-kinase pathway hyperactivation, p53 mutation, and dysregulation of wnt pathway. Many oncogenic pathways activate the mTOR pathway. mTOR has emerged as an effective target for colorectal cancer therapy. In vitro and preclinical studies targeting the mTOR pathway for colorectal cancer chemotherapy have provided promising perspectives. However, the overall objective response rates in major solid tumors achieved with single-agent rapalog therapy have been modest, especially in advanced metastatic colorectal cancer. Combination regimens of mTOR inhibitor with agents such as cytotoxic chemotherapy, inhibitors of vascular endothelial growth factor, epidermal growth factor receptor and Mitogen-activated protein kinase kinase (MEK) inhibitors are being intensively studied and appear to be promising. Further understanding of the molecular mechanism in mTOR signaling network is needed to develop optimized therapeutic regimens. In this paper, oncogenic gene alterations in colorectal cancer, as well as their interaction with the mTOR pathway, are systematically summarized. The most recent preclinical and clinical anticancer therapeutic endeavors are reviewed. New players in mTOR signaling pathway, such as nonsteroidal anti-inflammatory drug and metformin with therapeutic potentials are also discussed here. (C) 2014 Baishideng Publishing Group Co., Limited. All rights reserved.
引用
收藏
页码:4178 / 4188
页数:11
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