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

Published version
Peer-reviewed

Repository DOI


Type

Article

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Authors

Glaviano, Antonino 
Foo, Aaron SC 
Lam, Hiu Y 
Yap, Kenneth CH 
Jacot, William 

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.

Description

Keywords

AKT inhibitors, ATP-competitive mTOR inhibitors, Allosteric mTOR inhibitors, Bi-steric mTOR inhibitors, Cancer, Dual PI3K/mTOR inhibitors, Isoform-specific PI3K inhibitors, PDK1 inhibitors, PI3K/AKT/mTORC pathway, Pan PI3K inhibitors, Humans, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Signal Transduction, TOR Serine-Threonine Kinases, Neoplasms

Journal Title

Mol Cancer

Conference Name

Journal ISSN

1476-4598
1476-4598

Volume Title

22

Publisher

Springer Science and Business Media LLC