glucose regulation in mice.36 Consequently, in settings where p110 appears to be the critical CP-690550 Tofacitinib PI3K catalytic isoform mediating transformation, a p110 specific inhibitor may offer efficacy with decreased risk of insulin resistance compared with a pan PI3K inhibitor. ACTIVATION OF PI3K SIGNALING IN CANCER PI3K signaling is activated in human cancers via several different mechanisms.6,11 13 Increased PI3K signaling is often due to direct mutational activation or amplification of genes encoding key components of the PI3K pathway such as PIK3CA and AKT1, or loss of PTEN.6,9,12,37 41 Genetic alterations in several components of the PI3K signaling pathway have been reported and are summarized in Table 1.
PI3K also can be activated by genetic mutation and or amplification of upstream RTKs, and possibly by mutationally activated Ras.7,17 The mechanism of PI3K activation in an individual cancer may suggest the most effective type of therapeutic to inhibit the pathway. Somatic Alterations of PI3K Pathway Components in Cancer The most common genetic alteration of the PI3K signaling pathway Indirubin found in human cancer is inactivation of the PTEN tumor suppressor gene. Inactivation of PTEN leads to loss of its lipid phosphatase activity, causing accumulation of PIP3.56,57 The majority of somatic mutations in PTEN lead to protein truncation. However, missense mutations that typically abrogate PIP3 phosphatase activity are also commonly noted.58 While most PTEN mutations are sporadic, germline mutations in PTEN are noted in hereditary neoplastic disorders, such as Cowden disease.
59 Homozygous and hemizygous deletions of PTEN are also observed in human cancers. 38,45 Transcriptional repression and epigenetic silencing of PTEN, typically through promoter hypermethylation, is also a mechanism of PTEN inactivation.42,43 Because there are both genetic and epigenetic causes for PTEN loss, accurate assessment of a cancer,s PTEN status remains challenging and may ultimately require reliable measurements of protein expression. More recently, somatic mutations in PIK3CA have been identified in a variety of human tumors, including breast, colon, and endometrial cancers and glioblastomas.6,7,9,12,39 Mostof these mutations cluster to two hot spot regions in exons 9 and 20.6,12 Exon 20 encodes the catalytic domain of p110, and mutations in this domain may constitutively activate its enzymatic activity.
Exon 9 encodes the helical domain of p110, and these mutations de repress an inhibitory interaction between the N terminalSH2domain of p85 and the p110 catalytic subunit.60,61A smaller cluster of mutations is also found in the N terminal p85 interacting domain. Interestingly, these mutations increase the lipid kinase activity of p110 but do not appear to alter the interaction between p110 and p85.9,12 Expression of these PIK3CA mutants leads to increased oncogenic potential in vitro and in vivo.9,37 They cause constitutive signaling along t