Molecular Targeting of the Phosphoinositide-3-Protein Kinase (PI3K) Pathway across Various Cancers

Abstract

The dysregulation of the phosphatidylinositol-3-kinase (PI3K) pathway can lead to uncontrolled cellular growth and tumorigenesis. Targeting PI3K and its downstream substrates has been shown to be effective in preclinical studies and phase III trials with the approval of several PI3K pathway inhibitors by the Food and Drug Administration (FDA) over the past decade. However, the limited clinical efficacy of these inhibitors, intolerable toxicities, and acquired resistances limit the clinical application of PI3K inhibitors. This review discusses the PI3K signaling pathway, alterations in the PI3K pathway causing carcinogenesis, current and novel PI3K pathway inhibitors, adverse effects, resistance mechanisms, challenging issues, and future directions of PI3K pathway inhibitors.

The association between endometrial polyps and insulin resistance from the expression of PI3K and AKT proteins perspective

“…PI3K consists of a lipid kinase heterodimer, comprising a catalytic subunit p110 and an adaptor subunit p85, which participates in regulating essential cellular functions and diverse signaling cascades [ 25 , 26 ]. The double-enzymatic activity of PI3K acts to activate numerous signal proteins, including some oncoproteins.…”

“…On the other hand, AKT is a well-recognized target of PI3K and regulates various biological processes such as gene regulation, cellular growth and division, survival mechanisms, intracellular transport, and cancer initiation [ 25 – 28 ]. Abnormal activation of PI3K/AKT signal pathway can remarkably accelerate abnormal endometrial cell proliferation and apoptosis [ 23 , 24 , 26 , 28 ]. In this study, the expression scores and positive expression rates and mRNA expression levels of PI3K and AKT proteins were significantly higher in the EP group than in the non-EP group.…”

An Update on Physiopathological Roles of Akt in the ReprodAKTive Mammalian Ovary

“…As already introduced in the previous section, targeting the PI3K/Akt/mTOR pathway is a hot topic in the development of new OC therapies, as extensively reviewed elsewhere [ 110 , 111 , 143 , 144 , 145 , 146 ]. In this context, several strategies have been tested to prevent OC development through pan-PI3K inhibitors, isoform-specific inhibitors for PI3K, Akt, and mTORC1 and/or mTORC2, together with the dual pan-PI3K/mTORC1/mTORC2 inhibitors that inhibit at the same time the four main PI3K isoforms, mTORC1 and mTORC2 [ 146 ].…”