The phosphoinositide 3-kinase pathway in human cancer: genetic alterations and therapeutic implications

Abstract

The phosphoinositide 3-kinase (PI3K) pathway is frequently activated in human cancer and represents an attractive target for therapies based on small molecule inhibitors. PI3K isoforms play an essential role in the signal transduction events activated by cell surface receptors including receptor tyrosine kinases (RTKs) and G-protein-coupled receptors (GPCRs). There are eight known PI3K isoforms in humans, which have been subdivided into three classes (I-III). Therefore PI3Ks show considerable diversity and it remains unclear which kinases in this family should be targeted in cancer. The class I(A) of PI3K comprises the p110alpha, p110beta and p110delta isoforms, which associate with activated RTKs. In human cancer, recent reports have described activating mutations in the PIK3CA gene encoding p110alpha, and inactivating mutations in the phosphatase and tensin homologue (PTEN) gene, a tumour suppressor and antagonist of the PI3K pathway. The PIK3CA mutations described in cancer constitutively activate p110alpha and, when expressed in cells drive oncogenic transformation. Moreover, these mutations cause the constitutive activation of downstream signaling molecules such as Akt/protein kinase B (PKB), mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase (S6K) that is commonly observed in cancer cells. In addition to p110alpha, the other isoforms of the PI3K family may also play a role in human cancer, although their individual functions remain to be precisely identified. In this review we will discuss the evidence implicating individual PI3K isoforms in human cancer and their potential as drug targets in this context.

Fig. (1).

Signalling through the phosphatidylinositol 3-kinase (PI3K) affects cell growth, apoptosis and cell cycle regulation. The PI3K/Akt related pathways have a key role in initiating intracellular signalling cascades subsequent to the activation of membrane tyrosine kinases. The PI3K phosphorylates phosphatidylinositol-biphosphates (PIP₂), generating phosphatidylinositol-triphosphates (PIP₃). PIP₃ act as docking sites for Akt and PDK at the plasma membrane. Upon phosphorylation by PDK, AKT becomes activated and phosphorylates in turn several downstream proteins, regulating cell growth, survival, apoptosis and cell cycle. PTEN, phosphatase and tensin homolog deleted on chromosome 10; PDK, phosphoinositide-dependent kinases; GSK3, glycogen synthase kinase-3; MDM2, murine double minute; FKHR, forkhead; NF-κB, nuclear factor κB; Rheb, Ras homologue enriched in the brain; TSC1, TSC2, tuberous sclerosis complex 1 and 2; mTOR, mammalian target of rapamycin; 4EBP1, eukaryotic translation initiation factor 4E binding protein; S6K, S6 kinase.

Fig. (2).

Schematic of PIK3CA structure and “hot-spot” mutations observed in human cancers. Cancer-specific mutations are clustered in the helical and catalytic domain of p100α.Several mutations have been reported in human solid tumors for PIK3CA, the gene that encodes the catalytic subunit p110α of PI3K. High frequency of missense mutations is observed at the amino acid residues E542, E545 and H1047.