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

• Published in: Molecular cancer Vol. 22; no. 1; pp. 138 - 37
• Main Authors: Glaviano, Antonino, Foo, Aaron S C, Lam, Hiu Y, Yap, Kenneth C H, Jacot, William, Jones, Robert H, Eng, Huiyan, Nair, Madhumathy G, Makvandi, Pooyan, Geoerger, Birgit, Kulke, Matthew H, Baird, Richard D, Prabhu, Jyothi S, Carbone, Daniela, Pecoraro, Camilla, Teh, Daniel B L, Sethi, Gautam, Cavalieri, Vincenzo, Lin, Kevin H, Javidi-Sharifi, Nathalie R, Toska, Eneda, Davids, Matthew S, Brown, Jennifer R, Diana, Patrizia, Stebbing, Justin, Fruman, David A, Kumar, Alan P
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 18-08-2023; BioMed Central; BMC
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT inhibitors; AKT protein; Allosteric mTOR inhibitors; Antineoplastic drugs; Biochemistry, Molecular Biology; Bone cancer; Brain cancer; Breast cancer; Cancer; Care and treatment; Cell cycle; Cell growth; Cell survival; Cellular signal transduction; Cervical cancer; Clinical trials; Development and progression; Disease resistance; Dual PI3K/mTOR inhibitors; Estrogens; Gallbladder cancer; Gastric cancer; Genomics; Growth factors; Health aspects; Humans; Hyperactivity; Immunotherapy; Isoform-specific PI3K inhibitors; Kidney cancer; Kinases; Leukemia; Life Sciences; Lung cancer; Medical prognosis; Melanoma; Metastasis; Mutation; Neoplasms; Neoplasms - drug therapy; Neoplasms - genetics; Ovarian cancer; Pan PI3K inhibitors; Pharmaceutical sciences; Pharmacology; Phosphatidylinositol 3-Kinases; PI3K/AKT/mTORC pathway; Prostate cancer; Proto-Oncogene Proteins c-akt; PTEN protein; Review; Sarcoma; Signal Transduction; Thyroid cancer; TOR protein; TOR Serine-Threonine Kinases; Transcription factors; Tumors; PDK1 inhibitors; AKT inhibitors; Pan PI3K inhibitors; Allosteric mTOR inhibitors; Bi-steric mTOR inhibitors; Isoform-specific PI3K inhibitors; PI3K/AKT/mTORC pathway; ATP-competitive mTOR inhibitors; Dual PI3K/mTOR inhibitors; Cancer
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-023-01827-6

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.