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.
