Abstract
Gastric cancer and colorectal cancer are the leading cause of cancer mortality and have a dismal prognosis. The introduction of biological agents to treat these cancers has resulted in improved outcomes, and combination chemotherapy with targeted agents and conventional chemotherapeutic agents is regarded as standard therapy. Additional newly clarified mechanisms of oncogenesis and resistance to targeted agents require the development of new biologic agents. Aberrant activation of the inositide signaling pathway by a loss of function PTEN mutation or gain of function mutation/amplification of PIK3CA is an oncogenic mechanism in gastric cancer and colorectal cancer. Clinical trials with biologic agents that target the inositide signaling pathway are being performed to further improve treatment outcomes of patients with advanced gastric cancer and metastatic colorectal cancer (CRC). In this review we summarize the inositide signaling pathway, the targeted agents that inhibit abnormal activation of this signaling pathway and the clinical trials currently being performed in patients with advanced or metastatic gastric cancer and metastatic CRC using these targeted agents.
Highlights
Phosphoinositides are ubiquitous signaling molecules in eukaryotes that are modified by phosphorylation at multiple positions on phosphatidylinositol (PtdIns)
We focus on the phosphoinositide signaling system and possible targeted therapies in gastric cancer (GC) and colorectal cancer (CRC)
Activation of mTORC1 downstream of Akt/protein kinase B (PKB) subsequently phosphorylates substrates S6 kinase 1 (S6K1) and 4E-binding protein 1 (4E-BP1), which leads to initiation of mRNA translation and progression and stimulates protein synthesis. mTOR complex2 (mTORC2) consists of mammalian target of rapamycin (mTOR), rapamycin-insensitive companion of mTOR, mammalian lethal with SEC13 protein8 (MLST8), and mammalian stress-activated protein kinase interacting protein 1
Summary
Phosphoinositides are ubiquitous signaling molecules in eukaryotes that are modified by phosphorylation at multiple positions on phosphatidylinositol (PtdIns). PtdIns is a membrane phospholipid containing a hydrophobic diacylglycerol and water soluble inositol ring. Phosphorylation at different positions on the inositol ring results in seven phosphoinositides (Sasaki et al, 2009). The phosphoinositide signaling system is essential for regulating cellular processes, including cell proliferation, vesicle transport, and cytoskeletal remodeling. Deregulation of phosphoinositide signaling by altering the genes encoding phosphoinositide-modifying enzymes leads to many diseases, such as cancers, inflammatory bowel disease, rheumatic disease, diabetes, and others (Bunney and Katan, 2010; Raimondi and Falasca, 2012). We focus on the phosphoinositide signaling system and possible targeted therapies in gastric cancer (GC) and colorectal cancer (CRC)
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