TY - JOUR
T1 - Prospects of targeting PI3K/AKT/mTOR pathway in pancreatic cancer
AU - Mortazavi, Motahareh
AU - Moosavi, Fatemeh
AU - Martini, Miriam
AU - Giovannetti, Elisa
AU - Firuzi, Omidreza
N1 - Funding Information: Miriam Martini , PhD. is an Associate Professor of Applied Biology at the University of Torino, Department of Molecular Biotechnology and Health Sciences, and PI of the Cancer Cell Signaling Lab at the Molecular Biotechnology Center, Torino, Italy. She successfully requested funding from the Worldwide Cancer Research Foundation. She is the (co-)author of > 30 scientific publications in peer reviewed Journals (Scholar h-index, 24). Funding Information: The authors wish to thank the support of the Vice-Chancellor for Research , Shiraz University of Medical Sciences (Grant number: 25318 ). Funding Information: Elisa Giovannetti , MD, PhD, Clinical Pharmacologist. Associate Professor and Head of the “Molecular Mechanism of Drug Activity” group, Amsterdam UMC, VU University medical center, Department Laboratory Medical Oncology, Cancer Center Amsterdam, Amsterdam (Netherlands), and PI of the Cancer Pharmacology Lab, Fondazione Pisana per la Scienza (FPS), Pisa (Italy). She is actively involved, as elected chair, in research projects within the “Pharmacology” group of the EORTC (EORTC-PAMM). She successfully requested funding from the Netherlands Organization for Scientific Research (NWO, VENI grant), Marie Sklodowska Curie Actions and European Initiatives (H2020-MSCA-RISE “Alise” and COST “Stratagem”), AIRC (Start-Up and IG grants), CCA Foundation, and Dutch Cancer Society. Dr. Giovannetti is (co-)author of > 300 scientific publications in peer reviewed Journals (Scholar h-index, 59). Publisher Copyright: © 2022 Elsevier B.V.
PY - 2022/8/1
Y1 - 2022/8/1
N2 - Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses among all malignancies. PI3K/AKT/mTOR signaling pathway, a main downstream effector of KRAS is involved in the regulation of key hallmarks of cancer. We here report that whole-genome analyses demonstrate the frequent involvement of aberrant activations of PI3K/AKT/mTOR pathway components in PDAC patients and critically evaluate preclinical and clinical evidence on the application of PI3K/AKT/mTOR pathway targeting agents. Combinations of these agents with chemotherapeutics or other targeted therapies, including the modulators of cyclin-dependent kinases, receptor tyrosine kinases and RAF/MEK/ERK pathway are also examined. Although human genetic studies and preclinical pharmacological investigations have provided strong evidence on the role of PI3K/AKT/mTOR pathway in PDAC, clinical studies in general have not been as promising. Patient stratification seems to be the key missing point and with the advent of biomarker-guided clinical trials, targeting PI3K/AKT/mTOR pathway could provide valuable assets for treatment of pancreatic cancer patients.
AB - Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses among all malignancies. PI3K/AKT/mTOR signaling pathway, a main downstream effector of KRAS is involved in the regulation of key hallmarks of cancer. We here report that whole-genome analyses demonstrate the frequent involvement of aberrant activations of PI3K/AKT/mTOR pathway components in PDAC patients and critically evaluate preclinical and clinical evidence on the application of PI3K/AKT/mTOR pathway targeting agents. Combinations of these agents with chemotherapeutics or other targeted therapies, including the modulators of cyclin-dependent kinases, receptor tyrosine kinases and RAF/MEK/ERK pathway are also examined. Although human genetic studies and preclinical pharmacological investigations have provided strong evidence on the role of PI3K/AKT/mTOR pathway in PDAC, clinical studies in general have not been as promising. Patient stratification seems to be the key missing point and with the advent of biomarker-guided clinical trials, targeting PI3K/AKT/mTOR pathway could provide valuable assets for treatment of pancreatic cancer patients.
KW - Everolimus
KW - Gastrointestinal tumors
KW - Idelalisib
KW - Kinase inhibitors
KW - Personalized medicine
UR - http://www.scopus.com/inward/record.url?scp=85133398843&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.critrevonc.2022.103749
DO - https://doi.org/10.1016/j.critrevonc.2022.103749
M3 - Review article
C2 - 35728737
SN - 1040-8428
VL - 176
JO - Critical Reviews in Oncology/Hematology
JF - Critical Reviews in Oncology/Hematology
M1 - 103749
ER -