| First Author | Schmit F | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 17 | Pages | 6395-400 |
| PubMed ID | 24737887 | Mgi Jnum | J:208835 |
| Mgi Id | MGI:5565097 | Doi | 10.1073/pnas.1323004111 |
| Citation | Schmit F, et al. (2014) PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context. Proc Natl Acad Sci U S A 111(17):6395-400 |
| abstractText | There has been increasing interest in the use of isoform-selective inhibitors of phosphatidylinositide-3-kinase (PI3K) in cancer therapy. Using conditional deletion of the p110 catalytic isoforms of PI3K to predict sensitivity of cancer types to such inhibitors, we and others have demonstrated that tumors deficient of the phosphatase and tensin homolog (PTEN) are often dependent on the p110beta isoform of PI3K. Because human cancers usually arise due to multiple genetic events, determining whether other genetic alterations might alter the p110 isoform requirements of PTEN-null tumors becomes a critical question. To investigate further the roles of p110 isoforms in PTEN-deficient tumors, we used a mouse model of ovarian endometrioid adenocarcinoma driven by concomitant activation of the rat sarcoma protein Kras, which is known to activate p110alpha, and loss of PTEN. In this model, ablation of p110beta had no effect on tumor growth, whereas p110alpha ablation blocked tumor formation. Because ablation of PTEN alone is often p110beta dependent, we wondered if the same held true in the ovary. Because PTEN loss alone in the ovary did not result in tumor formation, we tested PI3K isoform dependence in ovarian surface epithelium (OSE) cells deficient in both PTEN and p53. These cells were indeed p110beta dependent, whereas OSEs expressing activated Kras with or without PTEN loss were p110alpha dependent. Furthermore, isoform-selective inhibitors showed a similar pattern of the isoform dependence in established Kras(G12D)/PTEN-deficient tumors. Taken together, our data suggest that, whereas in some tissues PTEN-null tumors appear to inherently depend on p110beta, the p110 isoform reliance of PTEN-deficient tumors may be altered by concurrent mutations that activate p110alpha. |
