Functional Characterization of an Isoform-Selective Inhibitor of PI3K-p110β as a Potential Anticancer Agent
| Autor: | Kurt W. Vogel, Thomas M. Roberts, Nathanael S. Gray, Coby B. Carlson, Jing Ni, Jean J. Zhao, Qingsong Liu, Cyril H. Benes, Michael J. Eck, Steve Riddle, Thanh Von, Shaozhen Xie |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Gene isoform Indazoles Mice Nude Antineoplastic Agents Biology Cell Line Mice Cell Line Tumor Neoplasms Animals Humans Protein Isoforms PTEN Enzyme Inhibitors Protein kinase B PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Sulfonamides Kinase PTEN Phosphohydrolase Class Ia Phosphatidylinositol 3-Kinase Tumor Burden Oncogene Protein v-akt Oncology Cell culture Immunology Cancer cell biology.protein Cancer research Female Neoplasm Transplantation |
| Zdroj: | Cancer Discovery. 2:425-433 |
| ISSN: | 2159-8290 2159-8274 |
| DOI: | 10.1158/2159-8290.cd-12-0003 |
| Popis: | Genetic approaches have shown that the p110β isoform of class Ia phosphatidylinositol-3-kinase (PI3K) is essential for the growth of PTEN-null tumors. Thus, it is desirable to develop p110β-specific inhibitors for cancer therapy. Using a panel of PI3K isoform-specific cellular assays, we screened a collection of compounds possessing activities against kinases in the PI3K superfamily and identified a potent and selective p110β inhibitor: KIN-193. We show that KIN-193 is efficacious specifically in blocking AKT signaling and tumor growth that are dependent on p110β activation or PTEN loss. Broad profiling across a panel of 422 human tumor cell lines shows that the PTEN mutation status of cancer cells strongly correlates with their response to KIN-193. Together, our data provide the first pharmacologic evidence that PTEN-deficient tumors are dependent on p110β in animals and suggest that KIN-193 can be pursued as a drug to treat tumors that are dependent on p110β while sparing other PI3K isoforms. Significance: We report the first functional characterization of a p110β-selective inhibitor, KIN-193, that is efficacious as an antitumor agent in mice. We show that this class of inhibitor holds great promise as a pharmacologic agent that could be used to address the potential therapeutic benefit of treating p110β-dependent PTEN-deficient human tumors. Cancer Discov; 2(5); 425–33. ©2012 AACR. Read the Commentary on this article by Shepherd and Denny, p. 393. This article is highlighted in the In This Issue feature, p. 377. |
| Databáze: | OpenAIRE |
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