Pathway activation through PI3K 1,2

PI3K plays a role in cell signaling and membrane trafficking 1

PI3K/AKT/mTOR image: PI3K activation leads to the production of PIP3 and subsequent activation of AKT

FOXO=Forkhead box O; GSK3=glycogen synthase kinase 3; mTORC=mammalian target of rapamycin complex; PDK1=phosphoinositide-dependent kinase-1; PI3K=phosphatidylinositol 3-kinase; PI4,5P2=phosphatidylinositol 4,5-bisphosphate; PIP3=phosphatidylinositol 3,4,5-trisphosphate; PTEN=phosphatase and tensin homolog; RTK=receptor tyrosine kinase.

Each of the 3 classes of phosphatidylinositol 3-kinases (PI3Ks) has its own substrate specificity, tissue distribution, and mechanism of action.3-5 Class I PI3Ks phosphorylate phosphatidylinositol 4,5-bisphosphate (PI4,5P2) to produce phosphatidylinositol 3,4,5-trisphosphate (PIP3), which mediates AKT activation. 2

Class I PI3Ks, which are present in all cell types, are comprised of 4 isoforms: p110α, p110β, p110δ, and p110γ.1,6 Although the 4 isoforms serve distinct functions based on cellular context (eg, p110δ and p110γ are mainly restricted to function in leukocytes), their activation leads to the production of PIP3, which mediates AKT activation through membrane recruitment by binding to its pleckstrin homology (PH) domain. 1,2

Somatic mutations in p110α have been identified in a variety of cancer types.5 These mutations increase kinase activity and contribute to transformation.7 Mutations in phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA), the gene coding for p110α, are prevalent in a diverse variety of cancer types, making PIK3CA the most commonly mutated oncogene. 4

Cancer types with a high prevalence of PIK3CA mutation include colorectal, uterine carcinosarcoma, and breast.8 The PI3K signaling pathway is altered in the majority of patients with advanced-stage prostate cancer, with biallelic loss of the tumor suppressor phosphatase and tensin homolog (PTEN) being the most common somatic mutation. 9

PI3K inhibition may block the growth of tumors activated by oncogenic receptor tyrosine kinases (RTKs), PI3K mutants, and/or PTEN loss of function. Inhibition strategies include adenosine triphosphate (ATP)-competitive pan-PI3K selective inhibitors, isoform-specific PI3K inhibitors, and inhibitors targeting isoform-specific PI3K mutations. 4,10


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