PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer

Molecular Cancer

Review

Richard D. Baird¹  Robert H. Jones²  Kevin H. Lin³  Matthew S. Davids³  Nathalie R. Javidi-Sharifi³  Jennifer R. Brown³  Eneda Toska⁴  Camilla Pecoraro⁵  Vincenzo Cavalieri⁵  Daniela Carbone⁵  Patrizia Diana⁵  Antonino Glaviano⁵  William Jacot⁶  David A. Fruman⁷  Birgit Geoerger⁸  Kenneth C. H. Yap⁹  Hiu Y. Lam⁹  Aaron S. C. Foo^1,10  Alan P. Kumar^1,11  Huiyan Eng^1,11  Gautam Sethi^1,11  Daniel B. L. Teh^1,12  Justin Stebbing^1,13  Madhumathy G. Nair^1,14  Jyothi S. Prabhu^1,14  Matthew H. Kulke^1,15  Pooyan Makvandi^1,16 

[1] Cancer Research UK Cambridge Centre, Hills Road, CB2 0QQ, Cambridge, UK;Cardiff University and Velindre Cancer Centre, Museum Avenue, CF10 3AX, Cardiff, UK;Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA;Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD, USA;Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy;Department of Medical Oncology, Institut du Cancer de Montpellier, Inserm U1194, Montpellier University, Montpellier, France;Department of Molecular Biology and Biochemistry, University of California, 216 Sprague Hall, Irvine, CA, USA;Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Inserm U1015, Université Paris-Saclay, Paris, France;Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore, Singapore;NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, 119077, Singapore, Singapore;Department of Surgery, National University Hospital Singapore, National University of Singapore, Singapore, Singapore;Department of Surgery, National University Hospital Singapore, National University of Singapore, Singapore, Singapore;Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore, Singapore;Departments of Ophthalmology and Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, and Neurobiology Programme, National University of Singapore, Singapore, Singapore;Division of Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, W12 0NN, London, UK;Division of Molecular Medicine, St. John’s Research Institute, St. John’s Medical College, 560034, Bangalore, India;Section of Hematology and Medical Oncology, Boston University and Boston Medical Center, Boston, MA, USA;The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, 324000, Quzhou, Zhejiang, China;

关键词: PI3K/AKT/mTORC pathway;    Pan PI3K inhibitors;    Isoform-specific PI3K inhibitors;    Dual PI3K/mTOR inhibitors;    AKT inhibitors;    Allosteric mTOR inhibitors;    ATP-competitive mTOR inhibitors;    Bi-steric mTOR inhibitors;    PDK1 inhibitors;    Cancer;   

DOI  :  10.1186/s12943-023-01827-6

 received in 2023-05-21, accepted in 2023-07-18,  发布年份 2023

来源: Springer

【 摘 要 】

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. 

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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