PI3K pathway

Class I phoshpatidylinositide-3-kinases (PI3Ks) are lipid kinases that function immediately downstream of the signaling of receptor tyrosine kinase including HER2, EGFR, and IGF-1R

A highly selective and potent small molecule inhibitor of the Delta and gamma  isoforms of phospho-3 kinase (PI3k).
The PI3K Family is categorized into three different classes who is members of for the differentiated based on the primary structure and substrate specificity.
The most therapeutically relevant are class I comprised of PI3K  alpha, beta, delta isoforms and class II which includes PI3K gamma isoform.
The alpha and beta isoforms are responsible for cellular proliferation and insulin signaling, respectively.

PI3Ks are heterodomers of a p110 catalytic subunit and a regulatory subunit.

The p110alpha and the p110beta catalytic subunits are encoded by PIK3CA and PIK3CB, respectively, and are expressed in all tissues.

The Delta and Gamma isoforms are overexpressed primarily in hematologic malignancies, inflammatory and autoimmune diseases.

The p110delta catalytic subunit is encoded by PIK3CD and is expressed in leukocytes.

This pathway is active in virtually all cancers, provoking tumors to adapt and become more aggressive.

PIK3CA Is mutated in 9% of human cancers.

It regulates cell growth, motility, survival, metabolism, and angiogenesis.

PI3K activation also triggers a survival signal due to activation of the AKT pathway.

PI3K is linked to cellular proliferation, motility, and survival of malignant B-cells in non-Hodgkin’s lymphoma.

The PI3K signaling cascade enhances nutrient uptake, macromolecule synthesis, and cell survival and is it frequent target of mutational events.

PI3K-AKT-mamamalian target of rapamycin (mTOR) Pathway is frequently altered in several human cancers.

The PI3K pathway is activated in two ways: 



PI3K can be activated downstream of RAS.



PI3K can be activated directly through a multifunctional docking site.



Activation of the PI3K pathway is associated with cell motility through altering extracellular matrix as well as localized recruitment of transducers involved in cytoskeletal reorganization.


Activation of the PI3K pathway is associated with cell motility through remodeling of adhesion to the extracellular matrix as well as localized recruitment of transducers involved in cytoskeletal reorganization, such as RAC1 and PAK. 



PI3K activation also triggers a survival signal due to activation of the AKT pathway.

Activation of the PI3K/AKT/mTOR  pathway contributes not only to the development of tumor but also involved in resistance to anti-cancer therapies.
In estrogen receptor positive breast cancer, mutations of PIK3CA represent the most common genetic events, occurring at a frequency of 30-50%.

The PI3K pathway is activated in a broad range of cancers, not just lymphoma.

PI3K-AKT mutation activation of this pathway contributes the endocrine resistance in breast cancer and represents a therapeutic target in this disease,

mTOR is a serine and threonine kinase downstream PI3K-AKT signaling, which nucleates 2 cellular complexes, mTORC1 and mTORC2 with distinct subunits and selectivity with cellular substrates.

The PI3K pathway is frequently altered in estrogen receptor positive breast cancer and has been implicated in resistance to endocrine therapy.

80% of cases of uterine cancer have abnormal PI3K pathway.

Increasing evidence exists that aberrant signaling through the phosphatidylinositol 3-kinase (PIK3A)-mamillion target of rapamycin (mTTOR) signaling pathway plays a critical role in endocrine resistance.

PI3K-AKT-mammalian target of rapamycin (mTOR) pathway is frequently altered in several human cancers.

Approximately 50% of estrogen receptor positive primary breast cancers show abnormal intrinsic activation of the PI3K-mTOR a pathway, and many patients with advanced for metastatic breast cancer develop acquired upregulation of the PI3K-mTOR signaling.

The PIK3CA, is mutated in approximately 40% of estrogen receptor positive breast cancers.

Activated cells must adapt their signaling and metabolism to drive cell division and meet the needs of a hyper proliferative state.

Alterations come in the form of direct mutational activation or amplification of genes encoding key components of the PI3K pathway, such as PIK3C and AKT1, or loss of PTEN.

Has important role in physiological processes, including insulin signaling, cell growth, immunity, and brain development.

Aliqopa (copanlisib) first agent approved as a PI3K inhibitor.

Approximately 40% of patients with hormone receptor positive, HER2 negative breast cancer have active mutations in the gene PIK3CA, inducing hyper activation of the Alpha iso form of phosphatidylinositol 3-kinase (PI3K).

Approximately 40% of patients HR positive breast cancer harbor PIK3CA mutation, which leads to a relative resistance to endocrine therapy.

PIK3CA mutation also leads to estrogen independent growth of HR positive breast cancer through hyperactivation of the PI3K pathway.

Alpelisib an oral small molecule, alpha specific PI3K inhibitor that selectively inhibits P110 alpha approximately 50 times as strongly as other isoforms.

Alpelisib is the first PI3K inhibitor to demonstrate a clinically meaningful benefit in treating patients with this type of breast cancer.

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