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.

Targeting Pancreatic Cancer with Novel Plumbagin Derivatives: Design, Synthesis, Molecular Mechanism, In Vitro and In Vivo Evaluation

“…These findings suggest that compound 3f is able to effectively inhibit the PI3K/Akt/mTOR signaling pathway in a short period of time and at relatively low concentrations, and thus indicate its strong potential as an anticancer agent. There are several known PI3K, Akt, and mTOR inhibitors that are being studied in clinical or preclinical settings for the treatment of pancreatic cancer and other types of cancer. ,− For example, mTOR inhibitors such as temsirolimus and everolimus have been shown to reduce the proliferation and survival of pancreatic cancer cells in vitro and in in vivo xenograft models . In addition, everolimus combined with octreotide was found to significantly improve progression-free survival in patients with advanced pancreatic neuroendocrine tumors in a phase III clinical trial .…”

“…5 Similarly, PI3K inhibitors such as BKM120 and GDC-0941 have also been shown to inhibit the growth of pancreatic cancer cells in vitro and in xenograft models, and to improve the response to chemotherapy. 35,36 BKM120 was found to have activity in patients with pancreatic cancer, with a response rate of 22% in a phase II clinical trial. 30 In this regard, disruption of the PI3K/ Akt/mTOR pathway suggest the strong potential of 3f as an anticancer agent for the clinical studies.…”

Caffeic acid, a dietary polyphenol pre-sensitizes PDAC to chemotherapeutic drug

“…KRAS mutations prevail in 90% of PDAC tumors, this protein is involved in cellular signalling from outside till the nucleus of the cell thus mutations in this in uence the entire functioning of cells [52]. Pi3K/AkT/mTOR signalling pathways in PDAC is often activated due to KRAS mutation leading to elevated cellular processes that help in growth, metabolism and survival [53]. This pathway is also involved in the initiation mechanisms of PDAC and inhibition of this is nowadays becoming popular with some therapies in preclinical and clinical trials [54].…”

Targeted therapy for pancreatic ductal adenocarcinoma: Mechanisms and clinical study

“… 51 , 52 Activated RAS drives the activation of downstream effector pathways such as the NF‐κB and phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT) pathways. 53 , 54 , 55 , 56 NF‐κB is a family of transcription factors that is primarily responsible for the triggering the inflammatory response in pancreatic cancer by upregulating the transcription of cytokines, chemokines, and other proinflammatory genes. 57 For example, activated NF‐κB enters the nucleus and promotes the transcription of IL‐6, IL‐8, and IL‐18, which further activates NF‐κB in a positive feedback loop.…”

“…Given that KRAS, a specific protein isoform of RAS, is the one of the earliest and most commonly mutated genes in PDAC, the RAS pathway plays a major role in PDAC initiation 51,52 . Activated RAS drives the activation of downstream effector pathways such as the NF‐κB and phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT) pathways 53–56 . NF‐κB is a family of transcription factors that is primarily responsible for the triggering the inflammatory response in pancreatic cancer by upregulating the transcription of cytokines, chemokines, and other proinflammatory genes 57 .…”