By the mechanism of PI3K pathway activation in a particular cancer. Finally, we will discuss the emerging data assessing the relative benefits of PI3K pathway inhibitors used as single agents versus combination therapies Fostamatinib R788 to treat cancer. PI3K SIGNALING CASCADE REGULATES CELL GROWTH AND SURVIVAL There are three classes of PI3Ks grouped according to structure and function. Class IA PI3K is the one most clearly implicated in human cancer.7 Class IA PI3Ks consist of a regulatory subunit and a catalytic subunit. Three mammalian genes, PIK3R1, PIK3R2, and PIK3R3, encode p85 , p85, and p55 regulatory subunits, respectively, which by convention are referred to collectively as p85.5,7,8 The catalytic isoforms, p110, p110, and p110, are the products of three genes, PIK3CA, PIK3CB, and PIK3CD.
5,8 As will be discussed in greater detail below, both PIK3CA and PIK3R1 are somatically mutated IkB Signaling in cancers, and these mutations promote activation of the PI3K pathway.9 12 Class IA PI3Ks are activated by growth factor stimulation through receptor tyrosine kinases.13 15 The regulatory subunit, p85, directly binds to phosphotyrosine residues on RTKs and or adaptors.16 This binding relieves the intermolecular inhibition of the p110 catalytic subunit by p85 and localizes PI3K to the plasma membrane where its substrate, phosphatidylinositol 4,5 bisphosphate, resides.15,16 PI3K can also be stimulated by activated Ras, which directly binds p110.17 Additionally, the p110 catalytic subunit can be activated by G protein coupled receptors.
8 PI3K phosphorylates PIP2 on the 3 OH position to produce PIP3. The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 dephosphoryates PIP3 to PIP2, thereby terminating PI3K dependent signaling. PIP3 propagates intracellular signaling by directly binding pleckstrin homology domains of various signaling proteins.18 PIP3 brings two PH domain containing serine threonine kinases, phosphoinositide dependent kinase 1 and AKT, into close proximity. PDK1 activates AKT by phosphorylating AKT at threonine 308.19 21 PI3K AKT signaling promotes cell growth and survival by several mechanisms. AKT promotes cell survival by inhibiting proapoptotic Bcl 2 family membersBADand BAX.5,18 AKTalso impedes negative regulation of the transcription factorNF B, leading to increased transcription of antiapoptotic and prosurvival genes.
22 Phosphorylation of Mdm2 by AKT antagonizes p53 mediated apoptosis, and AKT negatively regulates forkhead transcription factors, thereby reducing production of cell death promoting proteins.22 AKT also phosphorylates TSC2, thereby inhibiting the rheb GTPase activity of the TSC1 TSC2 dimer. Activated rheb stimulates the mammalian target of rapamycin containing protein complex mTORC1, leading to increased p70 S6 kinase activity.5 Activation of mTORC1results in increased protein synthesis by phosphorylation of eukaryotic initiation factor 4E and the ribosomal S6 protein.5 While mTORC1 r