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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Veröffentlicht in:PloS one 2012-11, Vol.7 (11), p.e49466
Hauptverfasser: 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
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container_issue 11
container_start_page e49466
container_title PloS one
container_volume 7
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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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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