Somatic mutations of PIK3R1 promote gliomagenesis
The phosphoinositide 3-kinase (PI3K) pathway is targeted for frequent alteration in glioblastoma (GBM) and is one of the core GBM pathways defined by The Cancer Genome Atlas. Somatic mutations of PIK3R1 are observed in multiple tumor types, but the tumorigenic activity of these mutations has not bee...
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creator | Quayle, Steven N Lee, Jennifer Y Cheung, Lydia W T Ding, Li Wiedemeyer, Ruprecht Dewan, Robert W Huang-Hobbs, Emmet Zhuang, Li Wilson, Richard K Ligon, Keith L Mills, Gordon B Cantley, Lewis C Chin, Lynda |
description | The phosphoinositide 3-kinase (PI3K) pathway is targeted for frequent alteration in glioblastoma (GBM) and is one of the core GBM pathways defined by The Cancer Genome Atlas. Somatic mutations of PIK3R1 are observed in multiple tumor types, but the tumorigenic activity of these mutations has not been demonstrated in GBM. We show here that somatic mutations in the iSH2 domain of PIK3R1 act as oncogenic driver events. Specifically, introduction of a subset of the mutations identified in human GBM, in the nSH2 and iSH2 domains, increases signaling through the PI3K pathway and promotes tumorigenesis of primary normal human astrocytes in an orthotopic xenograft model. Furthermore, we show that cells that are dependent on mutant P85α-mediated PI3K signaling exhibit increased sensitivity to a small molecule inhibitor of AKT. Together, these results suggest that GBM patients whose tumors carry mutant PIK3R1 alleles may benefit from treatment with inhibitors of AKT. |
doi_str_mv | 10.1371/journal.pone.0049466 |
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Somatic mutations of PIK3R1 are observed in multiple tumor types, but the tumorigenic activity of these mutations has not been demonstrated in GBM. We show here that somatic mutations in the iSH2 domain of PIK3R1 act as oncogenic driver events. Specifically, introduction of a subset of the mutations identified in human GBM, in the nSH2 and iSH2 domains, increases signaling through the PI3K pathway and promotes tumorigenesis of primary normal human astrocytes in an orthotopic xenograft model. Furthermore, we show that cells that are dependent on mutant P85α-mediated PI3K signaling exhibit increased sensitivity to a small molecule inhibitor of AKT. Together, these results suggest that GBM patients whose tumors carry mutant PIK3R1 alleles may benefit from treatment with inhibitors of AKT.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0049466</identifier><identifier>PMID: 23166678</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT protein ; Analysis of Variance ; Astrocytes ; Astrocytes - metabolism ; Biology ; Brain cancer ; Cancer ; Cancer genetics ; Cell Survival - drug effects ; Cell Transformation, Neoplastic - genetics ; Cell Transformation, Neoplastic - metabolism ; Class Ia Phosphatidylinositol 3-Kinase - genetics ; Dimethyl Sulfoxide - toxicity ; Dose-Response Relationship, Drug ; Endometrial cancer ; Genes ; Genetic aspects ; Genetics ; Genomes ; Genomics ; Glioblastoma ; Glioblastoma - genetics ; Gliomas ; Heterocyclic Compounds, 3-Ring - toxicity ; Humans ; Immunoblotting ; Kinases ; Medical research ; Medicine ; Mutagenesis ; Mutation ; Mutation - genetics ; Oncology ; Phosphatase ; Plasmids - genetics ; Proteins ; Signal transduction ; Signal Transduction - genetics ; Signaling ; Tumorigenesis ; Tumors ; Xenografts</subject><ispartof>PloS one, 2012-11, Vol.7 (11), p.e49466</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Quayle et al. 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Somatic mutations of PIK3R1 are observed in multiple tumor types, but the tumorigenic activity of these mutations has not been demonstrated in GBM. We show here that somatic mutations in the iSH2 domain of PIK3R1 act as oncogenic driver events. Specifically, introduction of a subset of the mutations identified in human GBM, in the nSH2 and iSH2 domains, increases signaling through the PI3K pathway and promotes tumorigenesis of primary normal human astrocytes in an orthotopic xenograft model. Furthermore, we show that cells that are dependent on mutant P85α-mediated PI3K signaling exhibit increased sensitivity to a small molecule inhibitor of AKT. Together, these results suggest that GBM patients whose tumors carry mutant PIK3R1 alleles may benefit from treatment with inhibitors of AKT.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>AKT protein</subject><subject>Analysis of Variance</subject><subject>Astrocytes</subject><subject>Astrocytes - metabolism</subject><subject>Biology</subject><subject>Brain cancer</subject><subject>Cancer</subject><subject>Cancer genetics</subject><subject>Cell Survival - drug effects</subject><subject>Cell Transformation, Neoplastic - genetics</subject><subject>Cell Transformation, Neoplastic - metabolism</subject><subject>Class Ia Phosphatidylinositol 3-Kinase - genetics</subject><subject>Dimethyl Sulfoxide - toxicity</subject><subject>Dose-Response Relationship, Drug</subject><subject>Endometrial cancer</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetics</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Glioblastoma</subject><subject>Glioblastoma - 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subjects | 1-Phosphatidylinositol 3-kinase AKT protein Analysis of Variance Astrocytes Astrocytes - metabolism Biology Brain cancer Cancer Cancer genetics Cell Survival - drug effects Cell Transformation, Neoplastic - genetics Cell Transformation, Neoplastic - metabolism Class Ia Phosphatidylinositol 3-Kinase - genetics Dimethyl Sulfoxide - toxicity Dose-Response Relationship, Drug Endometrial cancer Genes Genetic aspects Genetics Genomes Genomics Glioblastoma Glioblastoma - genetics Gliomas Heterocyclic Compounds, 3-Ring - toxicity Humans Immunoblotting Kinases Medical research Medicine Mutagenesis Mutation Mutation - genetics Oncology Phosphatase Plasmids - genetics Proteins Signal transduction Signal Transduction - genetics Signaling Tumorigenesis Tumors Xenografts |
title | Somatic mutations of PIK3R1 promote gliomagenesis |
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