Molecular Cancer (Aug 2023)
PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer
- Antonino Glaviano,
- Aaron S. C. Foo,
- Hiu Y. Lam,
- Kenneth C. H. Yap,
- William Jacot,
- Robert H. Jones,
- Huiyan Eng,
- Madhumathy G. Nair,
- Pooyan Makvandi,
- Birgit Geoerger,
- Matthew H. Kulke,
- Richard D. Baird,
- Jyothi S. Prabhu,
- Daniela Carbone,
- Camilla Pecoraro,
- Daniel B. L. Teh,
- Gautam Sethi,
- Vincenzo Cavalieri,
- Kevin H. Lin,
- Nathalie R. Javidi-Sharifi,
- Eneda Toska,
- Matthew S. Davids,
- Jennifer R. Brown,
- Patrizia Diana,
- Justin Stebbing,
- David A. Fruman,
- Alan P. Kumar
Affiliations
- Antonino Glaviano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo
- Aaron S. C. Foo
- Department of Surgery, National University Hospital Singapore, National University of Singapore
- Hiu Y. Lam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore
- Kenneth C. H. Yap
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore
- William Jacot
- Department of Medical Oncology, Institut du Cancer de Montpellier, Inserm U1194, Montpellier University
- Robert H. Jones
- Cardiff University and Velindre Cancer Centre
- Huiyan Eng
- Department of Surgery, National University Hospital Singapore, National University of Singapore
- Madhumathy G. Nair
- Division of Molecular Medicine, St. John’s Research Institute, St. John’s Medical College
- Pooyan Makvandi
- The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital
- Birgit Geoerger
- Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Inserm U1015, Université Paris-Saclay
- Matthew H. Kulke
- Section of Hematology and Medical Oncology, Boston University and Boston Medical Center
- Richard D. Baird
- Cancer Research UK Cambridge Centre
- Jyothi S. Prabhu
- Division of Molecular Medicine, St. John’s Research Institute, St. John’s Medical College
- Daniela Carbone
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo
- Camilla Pecoraro
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo
- Daniel B. L. Teh
- Departments of Ophthalmology and Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, and Neurobiology Programme, National University of Singapore
- Gautam Sethi
- Department of Surgery, National University Hospital Singapore, National University of Singapore
- Vincenzo Cavalieri
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo
- Kevin H. Lin
- Dana-Farber Cancer Institute, Harvard Medical School
- Nathalie R. Javidi-Sharifi
- Dana-Farber Cancer Institute, Harvard Medical School
- Eneda Toska
- Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health
- Matthew S. Davids
- Dana-Farber Cancer Institute, Harvard Medical School
- Jennifer R. Brown
- Dana-Farber Cancer Institute, Harvard Medical School
- Patrizia Diana
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo
- Justin Stebbing
- Division of Cancer, Imperial College London, Hammersmith Campus
- David A. Fruman
- Department of Molecular Biology and Biochemistry, University of California
- Alan P. Kumar
- Department of Surgery, National University Hospital Singapore, National University of Singapore
- DOI
- https://doi.org/10.1186/s12943-023-01827-6
- Journal volume & issue
-
Vol. 22,
no. 1
pp. 1 – 37
Abstract
Abstract The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.
Keywords
- PI3K/AKT/mTORC pathway
- Pan PI3K inhibitors
- Isoform-specific PI3K inhibitors
- Dual PI3K/mTOR inhibitors
- AKT inhibitors
- Allosteric mTOR inhibitors
