Targeting PI3K/AKT/mTOR Signaling Pathway in Pancreatic Cancer: From Molecular to Clinical Aspects

Abstract

Although pancreatic cancer (PC) was considered in the past an orphan cancer type due to its low incidence, it may become in the future one of the leading causes of cancer death. Pancreatic ductal adenocarcinoma (PDAC) is the most frequent type of PC, being a highly aggressive malignancy and having a 5-year survival rate of less than 10%. Non-modifiable (family history, age, genetic susceptibility) and modifiable (smoking, alcohol, acute and chronic pancreatitis, diabetes mellitus, intestinal microbiota) risk factors are involved in PC pathogenesis. Chronic inflammation induced by various factors plays crucial roles in PC development from initiation to metastasis. In multiple malignant conditions such as PC, cytokines, chemokines, and growth factors activate the class I phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) (PI3K/AKT/mTOR) signaling pathway, which plays key roles in cell growth, survival, proliferation, metabolism, and motility. Currently, mTOR, AKT, and PI3K inhibitors are used in clinical studies. Moreover, PI3K/mTOR dual inhibitors are being tested in vitro and in vivo with promising results for PC patients. The main aim of this review is to present PC incidence, risk factors, tumor microenvironment development, and PI3K/AKT/mTOR dysregulation and inhibitors used in clinical, in vivo, and in vitro studies.

Keywords: PI3K/AKT/mTOR; inhibitors; pancreatic cancer; risk factors; tumor microenvironment.

Figure 1

Anatomical and histological features of the pancreas: normal versus PADC.

Figure 2

Pancreatic PI3K/AKT/mTOR: normal versus pathological. In a healthy cell, such as a pancreatic cell, different ligands (growth factors, hormones, cytokines, or chemokines) bind to tyrosine kinase (RTKs) or G-protein receptors (GPCRs) located in the cell membrane, leading to PI3K activation by phosphorylation. Further, PI3K catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) at phosphatidylinositol 3,4,5-trisphosphate (PIP3), leading to AKT activation. AKT activation consists of two phosphorylation processes, one performed by mammalian target of rapamycin complex 2 (mTORC2) at serine 473 residue and the second one at threonine 308 residue performed by phosphoinositide-dependent kinase 1 (PDK1). Phosphorylated AKT induces further activation of mTOR and tuberous sclerosis protein 1 (TSC1) and TSC2 inhibition. In addition, mTOR phosphorylates ribosomal protein S6 kinases (S6K) and 4E-binding protein 1 (4E-BP1). The binding of growth factors to RTKs leads to Ras activation and in the end to extracellular signal-regulated kinase (ERK) activation, correlated with cell proliferation. Altogether, ERK and AKT activation are conducive to cell growth, proliferation, protein synthesis, autophagy, and apoptosis. In pancreatic cancer cells, besides growth factors, hormones, and cytokines, KRAS mutations activate PI3K and Ras. Moreover, these types of cells are characterized by PIK3CA mutations and PTEN loss. All these molecular events are associated with an overexpression of AKT phosphorylation, regarded as a pro-oncogenic factor. Together with ERK, AKT induces tumor growth, proliferation, migration, and invasion. “+”: activates, “−”: inhibits.

Figure 3

Pancreatic cancer pathogenesis: The pathogenesis of PC involves non- and modifiable risk factors that induce chronic inflammation mediated by several cell types. Chronic inflammation mediates TME development characterized by stromal desmoplastic reaction—the main PC histological hallmark, leading to fibrotic stoma formation, rich in type I collagen, fibronectin, and hyaluronic acid (HA). KRAS mutations may be activated by inflammation and modifiable risk factors such as diet and diabetes mellitus. Chronic inflammation and KRAS mutations are the main actors that induce PI3K/AKT/mTOR activation, contributing to PC-TME development, correlated with increased phosphorylated levels. Currently, the mentioned PI3K/AKT/mTOR inhibitors have been used in clinical studies. “+” activates.