Targeting the Akt/PI3K Signaling Pathway as a Potential Therapeutic Strategy for the Treatment of Pancreatic Cancer

Title:Targeting the Akt/PI3K Signaling Pathway as a Potential Therapeutic Strategy for the Treatment of Pancreatic Cancer

Volume: 24 Issue: 13

Author(s): Safieh Ebrahimi, Mina Hosseini, Soodabeh Shahidsales, Mina Maftouh, Gordon A. Ferns, Majid Ghayour-Mobarhan, Seyed Mahdi Hassanian*Amir Avan*

Affiliation:

• Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad,Iran

• Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad,Iran

Keywords: PI3K-AKT pathway, mTOR inhibitor, pancreatic cancer, resistance, PDAC, biomarkers.

Abstract: The phosphoinositide 3 kinase AKT mammalian target of rapamycin (PI3K-AKTmTOR) signaling pathway is an important in the aetiology of pancreatic cancer (PC) and is frequently activated in PC. It is then associated with a poorer prognosis. Aberrant activation of this pathway is involved in cell metabolism and survival, cell cycle progression, regulation of apoptosis, protein synthesis, and genomic instability. Several agents have been developed to target the Akt/PI3K pathways, including PI3K inhibitors, (e.g. LY294002, Wortmannin), PI3K/mTOR inhibitors (e.g. BEZ235), or Akt inhibitors (e.g. perifosine, MK2206), which have been tested alone or in combinations with DNA-targeted agents (e.g., gemcitabine and fluorouracil) in pancreatic ductal adenocarcinoma (PDAC). However, due to their unfavorable pharmaceutical activities, toxicity, and crossover inhibition of other lipid and protein kinases, these compounds have not been used in clinical studies. In this review, we focus on the progress in the development of Akt, PI3K and mTOR inhibitors for clinical applications, together with the need for the development of in PDAC and the need for the identification of predictive biomarkers and combination strategies with less toxicity in counteracting the mechanisms of resistance to the therapy.

Cite this article as:

Ebrahimi Safieh, Hosseini Mina, Shahidsales Soodabeh, Maftouh Mina, Ferns A. Gordon, Ghayour-Mobarhan Majid, Hassanian Mahdi Seyed*, Avan Amir*, Targeting the Akt/PI3K Signaling Pathway as a Potential Therapeutic Strategy for the Treatment of Pancreatic Cancer, Current Medicinal Chemistry 2017; 24 (13) . https://dx.doi.org/10.2174/0929867324666170206142658