title: Somatic mutations of PIK3R1 promote gliomagenesis.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Quayle
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Lee
authors.forename: Lydia W T
authors.initials: LW
authors.lastname: Cheung
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.forename: Ruprecht
authors.initials: R
authors.lastname: Wiedemeyer
authors.forename: Robert W
authors.initials: RW
authors.lastname: Dewan
authors.forename: Emmet
authors.initials: E
authors.lastname: Huang-Hobbs
authors.forename: Li
authors.initials: L
authors.lastname: Zhuang
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
mesh_terms: D000704:Analysis of Variance; D001253:Astrocytes / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics*; D004121:Dimethyl Sulfoxide / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005909:Glioblastoma / Q000235:genetics*; D006575:Heterocyclic Compounds, 3-Ring / Q000633:toxicity; D006801:Humans; D015151:Immunoblotting; D016296:Mutagenesis; D009154:Mutation / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D058543:Class Ia Phosphatidylinositol 3-Kinase; D004121:Dimethyl Sulfoxide