Targeting mTOR network in colorectal cancer therapy

Abstract

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 exquisite 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 non-steroidal anti-inflammatory drug and metformin with therapeutic potentials are also discussed here.

Keywords: Mechanistic target of rapamycin pathway; Colorectal cancer; Mechanistic target of rapamycin inhibitor; Chemotherapy; Drug resistance

Core tip: Mechanistic target of rapamycin (mTOR) pathway serves as a central regulating axis that coordinates cell growth and proliferation. Single-agent mTOR inhibition therapy, however, has provided only limited therapeutic efficacy towards colorectal cancer. Blocking compensatory pathways and multiple feedback loops is considered the challenge. Combination regimens are being intensively tested in clinic. This review summarizes extensive studies describing crosstalk between mTOR pathway and major oncogenic pathways contributing to colorectal cancer development and novel combinational strategies targeting the mTOR pathway in treating colorectal cancer are also introduced.