Although a variety of genetic alterations have been found across cancer types, the identification and functional characterization of candidate driver genetic lesions in an individual patient and their translation into clinically actionable strategies remain major hurdles.
Here, we use whole genome sequencing of a prostate cancer tumor, computational analyses, and experimental validation to identify and predict novel oncogenic activity arising from a point mutation in the phosphatase and tensin homolog (PTEN) tumor suppressor protein. We demonstrate that this mutation (p. A126G) produces an enzymatic gain-of-function in PTEN, shifting its function from a phosphoinositide (PI) 3-phosphatase to a phosphoinositide (PI) 5-phosphatase. Using cellular assays, we demonstrate that this gain-of-function activity shifts cellular phosphoinositide levels, hyperactivates the PI3K/Akt cell proliferation pathway, and exhibits increased cell migration beyond canonical PTEN loss-of-function mutants. These findings suggest that mutationally modified PTEN can actively contribute to well-defined hallmarks of cancer. Lastly, we demonstrate that these effects can be substantially mitigated through chemical PI3K inhibitors. These results demonstrate a new dysfunction paradigm for PTEN cancer biology and suggest a potential framework for the translation of genomic data into actionable clinical strategies for targeted patient therapy.
Proceedings of the National Academy of Sciences of the United States of America. 2015 Oct 26 [Epub ahead of print]
Helio A Costa, Michael G Leitner, Martin L Sos, Angeliki Mavrantoni, Anna Rychkova, Jeffrey R Johnson, Billy W Newton, Muh-Ching Yee, Francisco M De La Vega, James M Ford, Nevan J Krogan, Kevan M Shokat, Dominik Oliver, Christian R Halaszovich, Carlos D Bustamante
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;, Department of Neurophysiology, Philipps-Universität Marburg, 35037 Marburg, Germany;, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158; Howard Hughes Medical Institute, San Francisco, CA 94158;, Department of Neurophysiology, Philipps-Universität Marburg, 35037 Marburg, Germany;, Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158; J. David Gladstone Institutes, San Francisco, CA 94158. , Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158; J. David Gladstone Institutes, San Francisco, CA 94158. , Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;, Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;, Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158; J. David Gladstone Institutes, San Francisco, CA 94158. , Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158; Howard Hughes Medical Institute, San Francisco, CA 94158;, Department of Neurophysiology, Philipps-Universität Marburg, 35037 Marburg, Germany;, Department of Neurophysiology, Philipps-Universität Marburg, 35037 Marburg, Germany; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305