PI3K/AKT/mTOR pathway

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mTOR signaling pathway.

The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the

GSK3B,[2] and HB9.[5]

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

multipotency by self renewing and proliferating as opposed to differentiating and becoming quiescent. The PI3K/AKT pathway is crucial in this decision making process. NSCs are able to sense and respond to changes in the brain or throughout the organism. When blood glucose levels are elevated acutely, insulin is released from the pancreas. Activation of insulin receptors activates the PI3K/AKT pathway, which promotes proliferation.[3]
In this way, when there is high glucose and abundant energy in the organism, the PI3K/AKT pathway is activated and NSCs tend to proliferate. When there are low amounts of available energy, the PI3K/AKT pathway is less active and cells adopt a quiescent state. This occurs, in part, when AKT phosphorylates FOXO, keeping FOXO in the cytoplasm.
p27 and p21.[3] These tumor suppressors push the NSC to enter quiescence. FOXO knockouts lose the ability for cells to enter a quiescent state as well as cells losing their neural stem cell character, possibly entering a cancer like state.[3]

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

Shh. Shh works through a slow protein synthesis dependence, which stimulates other cascades that work synergistically with the PI3K/AKT pathway to induce proliferation. Then, the other pathway can be turned off and the effects of the PI3K/AKT pathway become insufficient in stopping differentiation.[2]
The specifics of this pathway are unknown.

Roles in cancer

Ovarian cancer

P27 expressions in OC cells. These data suggest a strong possibility of interaction and relevance of PIM kinases and the PI3K/AKT/mTOR network in the regulation of ovarian cancer.[9] However, targeting this pathway in ovarian cancer has been challenging with several trials failing to achieve sufficient clinical benefit.[10][11]

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

PIK3CA, loss of function or expression of phosphatase and tensin homolog (PTEN), and the proline-rich inositol polyphosphatase, which are downregulators of PI3K.[13] It is consistent with the hypothesis that PI3K inhibitors can overcome resistance to endocrine therapy when it is acquired[citation needed
]

Urothelial cancer

PIK3CA frequently have gain of function mutations in urothelial cancer.

E-cadherin loss. Specific isoform inhibitors to PI3Kb is a potential treatment for PTEN-deficient cancers.[16]

Prostate cancer

The PI3K pathway is a major source of drug resistance in

Gains in the nearby genetic region 3q26.31-32 have been shown to co-occur with a number of nearby PI3K family members including PIK3CA, PIK3CB and PIK3R4, leading to transcriptional changes in PIK3C2G, PIK3CA, PIK3CB, PIK3R4 as well as pathways associated with cell proliferation.[22] These large spanning gains associate with Gleason grade, tumour stage, lymph node metastasis and other aggressive clinical features.[22] In patients treated with PI3K inhibitors, those with copy number gains in PIK3CB appear to have increased drug susceptibility.[23]

Therapies

PI3K inhibitor

Pictilisib is another pan-PI3K inhibitor with greater subunitα-inhibitor activity than buparlisib.[13] Idelalisib is the first PI3K inhibitor approved by the US Food and Drug Administration and is utilized in the treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. Copanlisib is approved for relapsed follicular lymphoma in patients who have received at least two prior systemic therapies.[24] Duvelisib is approved for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and relapsed/refractory follicular lymphoma, both indications for patients who have received at least two prior therapies.[25]

Akt inhibitor

Akt
inhibition has focused on inhibition of two distinct binding sites:

  • 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 inhibition.[27] Gedatolisib is currently under development for the treatment of TNBC, in combination with PTK7 antibody–drug conjugate. Apitolisib (GDC-0980) is a PI3K inhibitor (subunits α, δ, and γ) that also targets mTORC [28]

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.

motor neurons regardless of the transplanted cells' microenvironment.[5] Following injury, neural stem cells enter a repair phase and express high levels of PI3K to enhance proliferation. This is better for survival of the neurons as a whole but is at the expense of generating motor neurons. Therefore, it can be difficult for injured motor neurons to recover their ability.[5] It is the purpose of modern research to generate neural stem cells that can proliferate but still differentiate into motor neurons. Lowering the effect of the PI3K pathway and increasing the effect of GSK3β and HB9 in NSCs is a potential way of generating these cells.[5]

PTEN inhibitors

PTEN is a tumor suppressor that inhibits the PI3K/AKT pathway. PTEN inhibitors, such as bisperoxovanadium,

axonogenesis.[7] Medicinal value of PTEN inhibitors remains to be determined.[citation needed
]

Long-term potentiation

In order for

tSNARE and Vam7. This directly leads to the docking of AMPA in the post synapse.[4] mTOR activated p70S6K and inactivated 4EBP1 which changes gene expression to allow LTP to occur.[8] Long-term fear conditioning training was affected in rats but there was no effect in short term conditioning. Specifically, amygdala fear conditioning was lost. This is a type of trace conditioning which is a form of learning that requires association of a conditioned stimulus with an unconditioned stimulus. This effect was lost in PI3K knockdowns and increased in PI3K overexpressions.[8]

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

References