Targeting PI3K/AKT/mTOR and MAPK Signaling Pathways in Gastric Cancer

Abstract

Gastric cancer (GC) is the fourth leading cause of death worldwide, with more than 1 million cases diagnosed every year. Helicobacter pylori represents the main risk factor, being responsible for 78% of the cases. Increased amounts of salt, pickled food, red meat, alcohol, smoked food, and refined sugars negatively affect the stomach wall, contributing to GC development. Several gene mutations, including PIK3CA, TP53, ARID1A, CDH1, Ras, Raf, and ERBB3 are encountered in GC pathogenesis, leading to phosphatidylinositol 3-kinase (PI3K) protein kinase B (AKT)/mammalian target of rapamycin (mTOR)-PI3K/AKT/mTOR-and mitogen-activated protein kinase (MAPK) signaling pathway activation and promoting tumoral activity. Helicobacter pylori, growth factors, cytokines, hormones, and oxidative stress also activate both pathways, enhancing GC development. In clinical trials, promising results have come from monoclonal antibodies such as trastuzumab and ramucirumab. Dual inhibitors targeting the PI3K/AKT/mTOR and MAPK signaling pathways were used in vitro studies, also with promising results. The main aim of this review is to present GC incidence and risk factors and the dysregulations of the two protein kinase complexes together with their specific inhibitors.

Keywords: MAPK; PI3K/AKT/mTOR; bacterial infection; dysregulation; gastric cancer; gene mutations; inhibitors.

Figure 1

Activation of PI3K/AKT/mTOR and MAPK signaling pathways. The binding of various growth factors, hormones, and cytokines to receptor tyrosine kinase (RTK) or G-protein-coupled receptors (GPCRs) leads to the activation of phosphatidylinositol 3-kinase (PI3K), which induces the phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2) to phosphatidylinositol (3,4,5)-triphosphate (PIP3), inducing protein kinase B (AKT) activation by phosphorylation by phosphoinositide-dependent kinase 1 (PDK1). Once activated, p-AKT activates other substrates by phosphorylation, such as the mammalian target of rapamycin (mTOR), glycogen synthase kinase-3 (GSK-3), the Forkhead box proteins (FoxOs) and c Adenosine monophosphate (cAMP) response binding protein (CREB). mTOR activates other proteins such as eukaryotic initiation factor binding protein 1 (4E-BP1) and ribosomal protein S6 kinase beta-1 (S6K), also known as p70S6 kinase. Mitogen-activated protein kinase (MAPK) complex activation starts with the formation of Ras-GTP from the inactive form Ras-GDP, which further activates the downstream substrates, including Raf, MAPK kinase (MAPKK or MEK), extracellular-signal-regulated kinases (ERK1/1), and c-jun N-terminal kinase or stress-activated protein kinase (JNK). In healthy cells, activation of these signaling pathways sustain the normal functions of the cells. Note: + denotes activation.

Figure 2

Phosphatidylinositol 3-kinase (PI3K) protein kinase B (AKT)/mammalian target of rapamycin (mTOR), PI3K/AKT/mTOR, and mitogen-activated protein kinase (MAPK) signaling pathway activation in gastric cancer (GC). Environmental factors, growth factors, genetic mutations, and infections with Helicobacter pylori and Epstein–Barr virus (EBV) activate both PI3K/AKT/mTOR and MAPK signaling pathways via receptor tyrosine kinases (RTKs). Further, PI3K is activated by phosphorylation, inducing the activation of AKT and downstream activation of other protein kinases such as the mammalian target of rapamycin (mTOR). In a similar manner, MAPK cascade is activated, and together with PI3K/AKT/mTOR, contributes to GC development, sustaining growth, survival, proliferation, angiogenesis, and metastasis. In clinical studies, several inhibitors of these protein kinases have been used. Therefore, PI3K, AKT, mTOR, MAPK kinase (MAPKK or MEK1/2), and human epithelial growth receptor 2 (HER2), showed different responses regarding the survival rate. Note: + denotes activation; − denotes inhibition.