that, in turn, directly binds and activates PI3K.65,68 70 Thus, when these cancers are successfully treated with EGFR and HER2 targeted therapies, respectively, PI3K signaling is turned off and the cells undergo cell death. Similarly, Cryptotanshinone glioblastomas frequently exhibit PI3K activation, either through integration of signaling from multiple activated RTKs, such as the constitutively active EGFRvIII mutant, or through the combined activation of RTKs and loss of PTEN.71,72 The small GTPase Ras is also frequently mutated in human cancers, and PI3K is an effector of Ras mediated oncogenic signaling. 73 Early studies showed that Ras directly bound p110, and provided a direct link between Ras and PI3K.
74 In addition, functional studies demonstrated that PI3K activation appears to be crucial for tumor initiation. For example, expression of a dominant negative p85 lacking Isoliquiritigenin the p110 binding domain inhibited Ras mediated transformation. 8,75 In addition, expression of a p110 mutant that does not directly bind Ras inhibited K Ras induced lung adenocarcinomas in genetically engineered mouse models.76 Similarly, deletion of Pik3r1 and Pik3r2 abrogated K Ras G12D induced lung tumorigenesis.65 Although PI3K activation may be necessary for K Ras induced tumorigenesis, preliminary studies suggest that inhibition of PI3K signaling alone may not be sufficient to shrink established tumors in vivo or effectively treat K Ras mutated cancer cell lines in vitro.65,77 These findings underscore the difference between killing established cancers and blocking tumorigenesis and cell transformation.
Furthermore, these studies suggest that established cancers with KRAS mutations may not be sensitive to single agent PI3K pathway inhibitors. Potential Roles for p110, p110, and p110 in Transformation While activating mutations in PIK3CA are frequently identified in human cancers, no oncogenic mutations have been verified in p110, p110, or the class IB catalytic isoform p110. Although rare somatic single residue substitutions have been found in p110 and p110 , the function of these substitutions is unknown. Despite the lack of evidence for activating mutations in these other p110 catalytic isoforms, recent work has demonstrated the oncogenic potential of p110, p110, and p110. Interestingly, unlike p110, overexpression of wild type p110, p110, or p110 is transforming in cell culture.
13 Although expression of the and isoforms is normally restricted to leukocytes, increased p110 has been identified in some colon and bladder cancers, as well as in glioblastomas.13 p110 appears to provide the critical PI3K activity in acute myelogenous leukemia, while p110 is upregulated by the Bcr Abl oncogene in chronic myelogenous leukemia.78,79 Recent data also suggest a prominent role for p110 in PTENdeficient tumors. Targeted deletion of pten in the mouse prostate results in prostatic intraepithelial neoplasia and carcinoma.80 Concomitant ablation of p110,