See ((PI3K pathway))
The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle.
This pathway is overactive in many malignancies, thus reducing apoptosis and allowing proliferation.
It is directly related to cellular quiescence, proliferation, cancer, and longevity.
Activation of the PI3K/AKT/mTOR pathway is one of the most common aberrations in human malignancies and is associated with tumor growth, survival, and drug resistance.
Approximately 50% of patients with castrate resistant prostate cancer have activation of this pathway due to the loss of phosphatase intention homolog (PTEN).
PI3K activation phosphorylates and activates AKT.
AKT downstream effects such as activating CREB, inhibiting p27, localizing FOXO in the cytoplasm, and activating mTOR.
The PI3K/AKT pathway is enhanced by EGF, shh, IGF-1, insulin, and CaM.
Leptin and insulin recruit PI3K signalling for metabolic regulation.
While multiple types of phosphoinositide 3-kinase exist, only class I are responsible for lipid phosphorylation in response to growth stimuli.
The pathway is antagonized by various factors including PTEN, GSK3B, and HB9.
This pathway is necessary, however, to promote growth and proliferation over differentiation of adult stem cells, and neural stem cells.
This pathway has been found to be a necessary component in neural long term potentiation.
The PI3K/AKT pathway is crucial to neural stem cells (NSCs) finding a balance between maintaining their multipotency by self renewing and proliferating as opposed to differentiating and becoming quiescent this decision making process.
When glucose levels are high, insulin and therefore IGF is produced, signaling activates the PI3K/AKT pathway which works to promote proliferation.
High glucose and high energy activates the PI3K/AKT pathway and NSCs tend to proliferate.
When there is low amounts of available energy, the PI3K/AKT pathway is less active and cells adopt a quiescent state.
The PI3K/AKT pathway has a natural inhibitor PTEN, whose function is to limit proliferation in cells, helping to prevent cancer.
Cells that overexpress AKT increase the amount of proliferation compared to wild type cells.
CREB is a transcription factor that influences the transcription of cyclin A which promotes proliferation.
Shh works through a slow protein synthesis dependence, and works synergistically with the PI3K/AKT pathway to induce proliferation.
PI3K/ AKT/mTOR pathway is a central regulator of ovarian cancer.
PIM kinases are directly and indirectly found to activate mTOR,are over expressed in many types of cancers and they also contribute to the regulation of ovarian cancer.
There is close interaction of PIM with PI3K/ AKT/mTOR cascade and its components.
Breast cancer aberrations in the PI3K/AKT/mTOR pathway are common genomic abnormalities.
Breast cancer aberrations include the PIK3CA gene mutation and the loss-of-function mutations or epigenetic silencing of phosphatase and tensin homologue (PTEN).
Approximately 30-40% of breast cancers are activated by the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway.
In triple negeative breast cancer activation of the PI3K/AKT/mTOR pathway can happen as a function of overexpression of upstream regulators like EGFR, activating mutations of PIK3CA, loss of function or expression of phosphatase and tensin homolog (PTEN), and the proline-rich inositol polyphosphatase, which are downregulators of PI3K.
PI3K inhibitors can overcome resistance to endocrine therapy when it is acquired
PIK3CA is frequently associated with a gain of function mutation in urothelial cancer.
PI3Kb is involved in the activation of platelets and development of thrombotic diseases.
PI3Kb contributes to tumor proliferation.
PI3K has an important role in tumorigenesis in PTEN-negative cancers.
Altering the gene for PI3Kb might be a therapeutic approach for cancers with mutant PTEN and E-cadherin loss.
PI3K inhibitors may overcome drug resistance advanced breast cancer.
There are different PI3K inhibitors exhibit different effect against various PI3K types.
((Idelalisib)) is the first PI3K inhibitor approved.
Idelalisib 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.
((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.
There are three Akt isozymes, Akt1, Akt2 and Akt3.
There is a high prevalence of Akt1 activating mutations in 4–6% of breast cancers and 1–2% of colorectal cancer.
There is significant correlation of phosphorylated mTOR with the survival rate for patients with stages I and II TNBC.
Blockage of the PI3K/AKT/mTOR pathway can lead to increased antitumor activity in TNBC.
Soultaneous targeting of PI3K and mTOR leads to significant inhibition of receptor tyrosine kinase-positive feedback loops seen with isolated PI3K inhibition.
Numerous cell signalling pathways that exhibit cross-talk with the PI3K pathway, potentially allowing cancer cells to escape inhibition of PI3K.
Inhibition of the PI3K pathway with other targets provide a synergistic response: PI3K and MEK co-targeted inhibition in lung cancer cells.
Combining PI3K inhibition with chemotherapy may also offer improved response over inhibition of PI3K alone.
PTEN is a natural inhibitor of the PI3K/AKT pathway.
PI3K-AKT signaling pathway also has an important role in brain growth, as
intracranial volume is also associated with this pathway.
Thyroid hormone produces some of its effects on the maturation and plasticity of synapses of the brain through PI3K.