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

被引：527

作者：

Glaviano, Antonino ^{[1
]}

Foo, Aaron S. C. ^{[2
]}

Lam, Hiu Y. ^{[3
,4
]}

Yap, Kenneth C. H. ^{[3
,4
]}

Jacot, William ^{[5
]}

Jones, Robert H. ^{[6
,7
]}

Eng, Huiyan ^{[2
,3
]}

Nair, Madhumathy G. ^{[8
]}

Makvandi, Pooyan ^{[9
]}

Geoerger, Birgit ^{[10
]}

Kulke, Matthew H. ^{[11
,12
]}

Baird, Richard D. ^{[13
]}

Prabhu, Jyothi S. ^{[8
]}

Carbone, Daniela ^{[1
]}

Pecoraro, Camilla ^{[1
]}

Teh, Daniel B. L. ^{[14
,15
,16
]}

Sethi, Gautam ^{[2
,3
]}

Cavalieri, Vincenzo ^{[1
]}

Lin, Kevin H. ^{[17
]}

Javidi-Sharifi, Nathalie R. ^{[17
]}

Toska, Eneda ^{[18
]}

Davids, Matthew S. ^{[17
]}

Brown, Jennifer R. ^{[17
]}

Diana, Patrizia ^{[1
]}

Stebbing, Justin ^{[19
]}

Fruman, David A. ^{[20
]}

Kumar, Alan P. ^{[2
,3
]}

机构：

[1] Univ Palermo, Dept Biol Chem & Pharmaceut Sci & Technol, I-90123 Palermo, Italy

[2] Natl Univ Singapore, Natl Univ Singapore Hosp, Dept Surg, Singapore, Singapore

[3] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, Singapore 117600, Singapore

[4] Natl Univ Singapore, Yong Loo Lin Sch Med, NUS Ctr Canc Res N2CR, Singapore 119077, Singapore

[5] Univ Montpellier, Inst Canc Montpellier, Dept Med Oncol, Inserm U1194, Montpellier, France

[6] Cardiff Univ, Museum Ave, Cardiff CF10 3AX, Wales

[7] Velindre Canc Ctr, Museum Ave, Cardiff CF10 3AX, Wales

[8] St Johns Res Inst, Div Mol Med, St Johns Med Coll, Bangalore 560034, Karnataka, India

[9] Wenzhou Med Univ, Quzhou Peoples Hosp, Quzhou Affiliated Hosp, Quzhou 324000, Zhejiang, Peoples R China

[10] Univ Paris Saclay, Gustave Roussy Canc Ctr, Dept Pediat & Adolescent Oncol, Inserm U1015, Paris, France

[11] Boston Univ, Sect Hematol & Med Oncol, Boston, MA USA

[12] Boston Med Ctr, Boston, MA USA

[13] Canc Res UK Cambridge Ctr, Hills Rd, Cambridge CB2 0QQ, England

[14] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore

[15] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Anat, Singapore, Singapore

[16] Natl Univ Singapore, Neurobiol Programme, Singapore, Singapore

[17] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA

[18] Johns Hopkins Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD USA

[19] Imperial Coll London, Div Canc, Hammersmith Campus,Cane Rd, London W12 0NN, England

[20] Univ Calif Irvine, Dept Mol Biol & Biochem, 216 Sprague Hall, Irvine, CA USA

来源：

MOLECULAR CANCER | 2023年 / 22卷 / 01期

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; RENAL-CELL CARCINOMA; FOXO TRANSCRIPTION FACTORS; ADVANCED BREAST-CANCER; PHASE-I TRIAL; PHOSPHATIDYLINOSITOL 3-KINASE INHIBITOR; NONFUNCTIONAL NEUROENDOCRINE TUMORS; CHRONIC LYMPHOCYTIC-LEUKEMIA; INTRAVENOUS PI3K INHIBITOR; PROTEIN-COUPLED RECEPTORS; HEPATOCYTE GROWTH-FACTOR;

D O I：

10.1186/s12943-023-01827-6

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

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.

引用

页数：37

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