PI3K/AKT/mTOR pathway
The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the
In many cancers, this pathway is overactive, thus reducing
Proliferation of neural stem cells
Response to glucose
Neural stem cells (NSCs) in the brain must find a balance between maintaining their
PTEN
The PI3K/AKT pathway has a natural inhibitor called Phosphatase and tensin homolog (PTEN) whose function is to limit proliferation in cells, helping to prevent cancer. Knocking out PTEN has been shown to increase the mass of the brain because of the unregulated proliferation that occurs.[3] PTEN works by dephosphorylating PIP3 to PIP2 which limits AKTs ability to bind to the membrane, decreasing its activity. PTEN deficiencies can be compensated downstream to rescue differentiation or quiescence. Knocking out PTEN is not as serious as knocking out FOXO for this reason.[3]
CREB
The cAMP response element
Roles in cancer
Ovarian cancer
Breast cancer
In many kinds of breast cancer, aberrations in the PI3K/AKT/mTOR pathway are the most common genomic abnormalities. The most common known aberrations include the
Urothelial cancer
PIK3CA frequently have gain of function mutations in urothelial cancer.
Prostate cancer
The PI3K pathway is a major source of drug resistance in
Therapies
PI3K inhibitor
Akt inhibitor
- the allosteric pocket of the inactive enzyme, and
- the ATP binding site.
Allosteric Akt inhibitors, highlighted by MK-2206, have been extensively evaluated in a clinical setting; Recently, additional allosteric Akt inhibitors have been identified. ARQ-092, is a potent pan-Akt inhibitor which can inhibit tumor growth preclinically and is currently in Phase I clinical studies.[26]
mTOR inhibitor
There is significant correlation of phosphorylated mTOR with the survival rate for patients with stages I and II TNBC. A patient-derived xenograft TNBC model testing the mTOR inhibitor rapamycin showed 77–99% tumor-growth inhibition, which is significantly more than has been seen with doxorubicin; protein phosphorylation studies indicated that constitutive activation of the mTOR pathway decreased with treatment.[13]
Dual PI3K/AKT/mTOR inhibitors
It has been hypothesized that blockage of the PI3K/AKT/mTOR pathway can lead to increased antitumor activity in TNBC. Preclinical data have shown that the combination of compounds targeting different cognate molecules in the PI3K/AKT/mTOR pathway leads to synergistic activity. On the basis of these findings, new compounds targeting different components of the PI3K/AKT/mTOR pathway simultaneously continue to be developed. For example, gedatolisib inhibits mutant forms of PI3K-α with elevated kinase activity at concentrations equivalent to the IC50 for wild-type PI3K-α. PI3K-β, -δ and -γ isoforms were inhibited by gedatolisib at concentrations approximately 10-fold higher than those observed for PI3K-α.
PI3K pathway co-targeted therapy
There are numerous cell signalling pathways that exhibit cross-talk with the PI3K pathway, potentially allowing cancer cells to escape inhibition of PI3K.[29] As such, inhibition of the PI3K pathway alongside other targets could offer a synergistic response, such as that seen with PI3K and MEK co-targeted inhibition in lung cancer cells.[30] More recently, co-targeting the PI3K pathway with PIM kinases has been suggested, with numerous pre-clinical studies suggesting the potential benefit of this approach.[31][32] Development of panels of cell lines that are resistant to inhibition of the PI3K pathway may lead to the identification of future co-targets, and better understanding of which pathways may compensate for loss of PI3K signalling following drug treatment.[33] Combined PI3K inhibition with more traditional therapies such as chemotherapy may also offer improved response over inhibition of PI3K alone.[34]
Neural stem cells
The type of growth factor signaling can effect whether or not NSCs differentiate into motor neurons or not. Priming a media with FGF2 lowers the activity of the PI3K/AKT pathway, which activates GSK3β. This increases expression of HB9.
PTEN inhibitors
PTEN is a tumor suppressor that inhibits the PI3K/AKT pathway. PTEN inhibitors, such as bisperoxovanadium,
Long-term potentiation
In order for
Role in brain growth
In addition to its role in synaptic plasticity described above, PI3K-AKT signaling pathway also has an important role in brain growth, which is altered when PI3K signaling is disturbed. For example, intracranial volume is also associated with this pathway, in particular with AKT3 intronic variants.[39] Thyroid hormone was originally identified as the primary regulator of brain growth and cognition, and recent evidence has demonstrated that thyroid hormone produces some of its effects on the maturation and plasticity of synapses through PI3K.[40]
See also
- AKT inhibitor
- Akt/PKB signaling pathway
- mTOR inhibitor
- PI3K inhibitor
- PTEN
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