factors and therefore seem to obviate the usual obligate interactions with tyrosine phosphorylatedRTKsand or adapters. Thus, it is intriguing that some studies have suggested that the presence of these mutations Crenolanib CP-868569 confers resistance to therapies targeting RTKs.44,62 Expressing mutated PIK3CA in fibroblasts and mammary epithelial cells results in transformation, growth factor independent proliferation, and resistance to apoptosis.9,63,64 Additionally, transgenic mice with lung specific induction of the kinase domain mutant p110 H1047R develop lung adenocarcinomas.65 In addition to these activating mutations, amplification of PIK3CA is also observed frequently in ovarian cancer and other tumors, but how amplification affects PI3K activation is less clear.
39 Mutations AMPA Receptor in the p85 regulatory subunit PIK3R1 are also observed in a variety of human cancers, including glioblastomas, ovarian cancers, and colorectal cancers.10,11 Mutations in PIK3R1 generally produce either truncations or in frame deletions that often localize to the inter SH2 domain of p85. Structural analyses suggest that the iSH2 domain of p85 interacts with the C2 domain of p110.60 Thus, it seems likely that these p85 mutations also activate PI3K signaling by relieving the inhibitory effect of p85 on p110.11,66 Laboratory studies suggest that these mutations also lead to constitutive PI3K signaling.11,66 Mutations in AKT family genes encoding for AKT1, AKT2, and AKT3have also been identified inhumancancers.
Asingle amino acid substitution, E17K, in the lipid bindingPHdomain ofAKT1has been identified in breast, colorectal, endometrial, and ovarian cancers, as well as melanoma.40,50,51 This amino acid change alters AKT1 lipid binding, presumably leading to constitutive membrane localization in the absence of PIP3. However, although phosphorylation on Ser473 was constitutive in this mutant, T308 phosphorylation was still responsive to PI3K activation.50 Thus, it is unclear if PI3K inhibitors will effectively decrease AKT signaling in cancers with these mutations. The E17K mutation has also been identified in AKT3 in some melanomas. 51 In addition, mutations affecting the kinase domain of AKT2 have been found in colorectal cancers, however, the functional consequences of these mutations have not been assessed.52 Amplification of AKT2 has also been reported in human tumors.
53,54 PI3K Activation by Receptor Tyrosine Kinases and Ras In normal epithelial cells, PI3K is often activated downstream of RTKsignaling. In cancers, theseRTKsare often mutated, amplified, or overexpressed, causing aberrant PI3K activation. When therapies targeting RTKs are effective, they invariably lead to loss of PI3K signaling. 67 For example, PI3K is activated by epithelial growth factor receptor in lung cancers harboring somatic activating mutations in EGFR, and by human epidermal growth factor receptor 2 in breast cancers with HER2 amplification.65,68 70 In these cancers, EGFR