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The Role of the Phosphatidylinositol-5-Phosphate 4-Kinases in p53-Null Breast Cancers

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Technical Report,30 Sep 2014,29 Sep 2015

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Weill Cornell Medicine New York United States

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I have identified a family of druggable enzymes whose loss of function results in synthetic lethality with p53 loss. Prior to my observation of this synthetic lethality, these enzymes were not a focus for oncology research. My preclinical studies in genetically engineered mouse models and in human breast cancer cell lines and xenografts indicate complete inhibition of cell growth upon loss of these enzymes in the context of p53 mutation or deletion, but no effect on growth in cells containing functional p53. As I mentioned above through an R03 grant we have screened a library of drug-like molecules and identified a number of highly specific inhibitors of PI5P4K. Additionally, through the collaboration with Dr. Nathanael Grays laboratory Dana Farber Cancer Institute to develop covalent inhibitors of PI5P4K we have demonstrated compounds that cause 95 inhibition of PI5P4K.These compounds provide me with tools for interrogating the mechanism of synthetic lethality and for exploring in vivo efficacytoxicity in my mouse models. With all these tools in hand I am well equipped to tackle key questions surrounding the role of these essential enzymes not only in cancer biology but in normal biological processes.

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