PI3K signaling in glioma--animal models and therapeutic challenges

Abstract

The PI3 kinase (PI3K) family plays a complex role in cell biology and metabolism. Signaling through the PI3Ks is frequently activated in many human cancers, including glioblastoma, because of gain-of-function mutations in PIK3CA or loss of PTEN. Experiments involving genetic mouse models and small molecule inhibitors have helped to elucidate the roles of the regulatory and catalytic subunits of PI3K in metabolism and cancer. Downstream of PI3K is Akt, a critical effector of growth, proliferation and survival. The suggested dependence of glioblastoma tumors on PI3K signaling implies that PI3K inhibitors should lead to effective killing of these cancer cells, but that has been shown not to be the case. The engagement of other survival pathways in response to PI3K inhibition prompts the need to develop combination therapies that promote cytotoxicity in cancer cells.

Figure 1

The roles of P110 isoforms. The isoforms of the class I p110 catalytic subunit serve different cellular functions. Of the four, p110 alpha has been most widely implicated in human cancers, in addition to its role in cell proliferation and metabolism. P110 beta has also been shown to have a role in growth and metabolism, while p110 gamma and p110 delta have immune functions. RTK = receptor tyrosine kinase; PIP2 = phosphatidylinositol (4,5)‐bisphosphate; PIP3 = phosphatidylinositol(3,4,5)‐trisphosphate.

Figure 2

Activation of class I PI3Ks. Class I PI3 kinases are activated by upstream signals from receptor tyrosine kinases (RTKs). Activated PI3 kinase catalyzes the production of the second messenger (phosphatidylinositol(3,4,5)‐trisphosphate) PIP3 from phosphatidylinositol (4,5)‐bisphosphate (PIP2), which recruits the Akt protein kinase to the membrane. The phosphatase and tensin homolog deleted from chromosome 10 (PTEN) acts as a critical negative regulator of PI3K signaling by removing the D3 phosphate from PIP3 to produce PIP2.

Figure 3

Downstream of PI3 kinase. Phosphorylation of Akt by PDK1 and a feedback loop involving the mammalian target of rapamycin (mTOR)‐rictor complex resulting in the activation of Akt leads to the phosphorylation of multiple downstream substrates that regulate various cellular processes. RTK = receptor tyrosine kinase; GSK = glycogen synthase kinase; TSC = tuberous sclerosis complex; PIP2 = phosphatidylinositol (4,5)‐bisphosphate; PIP3 = phosphatidylinositol(3,4,5)‐trisphosphate.