ESMO E-Learning: PI3K/Akt/mTOR Pathway
- To provide a basic introduction in the preclinical data relevant for the understanding of functional mechanisms in the PI3K/Akt/mTOR pathway
- To understand basic concepts of translating preclinical observations in the PI3K/Akt/mTOR signalling into clinical setting
- To summarise the current status and clinical perspective in a range of malignant diseases from data on targeting all axes of the PI3K/Akt/mTOR pathway
|Title||Duration||Content||CME Points||CME Test|
|PI3K/Akt/mTOR pathway||23 min.||37 slides||1||Take Test|
The PI3K/Akt/mTOR pathway is a key signalling pathway controlling several physiological functions such as growth, survival and metabolism of the cells. The pathway is altered in several tumours where it is constitutively activated.
This E-learning module analyses the structure and functions of the key factors participating in the pathway and their main alterations found in human tumours. Particular emphasis will be given to drugs acting against PI3Ks, Akt and mTOR, for which evidences of activity have been presented.
The PI3Ks are members of a conserved family of intracellular lipid Kinases that phosphorylate the 3’-hydroxyl group of phosphatidylinositol and phosphoinositides. PI3Ks are grouped into three classes, I, II and III according to their substrate preference and sequence homology. Class I of PI3Ks is the most studied. Activation of PI3K leads to the generation of PIP3, a lipid second messenger that activates many downstream molecules by binding to their PH domains. The protein Akt, also known as PKB, is the principal target of PIP3. Interaction of PIP3 with Akt results in Akt membrane recruitment and subsequent Phosphorylation of Akt by PI3K-dependent kinase-1 (PDK1) and PI3K-dependent kinase-2 (PDK2). Activated Akt is in turn able to phosphorylate many target proteins and regulate many cellular functions. The main consequences of Akt activation, relevant to cancer, are cell survival, cell proliferation and cell growth. Among the downstream effectors, an important role is played by the mammalian target of rapamycin (mTOR). mTOR is present in two distinct complexes inside the cells, a rapamycin and nutrient-sensitive multiprotein complex (mTORC1) and a growth factor sensitive but nutrient insensitive and rapamycin insensitive complex (mTORC2). Interestingly, mTOR, when assembled in the mTORC2 complex, is able to phosphorylate Akt thus suggesting that mTOR can function either upstream or downstream to Akt.
The PI3K pathway is physiologically activated by many growth factors and regulators. Whatever the mechanism, activation of the PI3K pathway results in a disturbance of control of cell growth and survival, which contribute to a growth advantage. This pathway is therefore an attractive target for the development of novel anticancer strategies.
Several molecules are being tested for their ability to inhibit the PI3K/Akt/mTOR pathway. There are available molecules with high specificity for specific Isoforms of PI3K, molecules with pan inhibitory activity as well as dual inhibitors able to simultaneously block the activity of two members of the same pathway.
One of the major challenges is to identify which tumour is likely to respond to this class of molecules and which Biomarker, if any, can be of help for the identification of these potentially responding tumours.
This module summarises the evidences available so far both at preclinical and clinical level.
The authors have reported no conflicts of interest.