Somatic Mutations of PIK3R1 Promote Gliomagenesis

Steven N. Quayle, Jennifer Y. Lee, Lydia W.T. Cheung, Li Ding, Ruprecht Wiedemeyer, Robert W. Dewan, Emmet Huang-Hobbs, Li Zhuang, Richard K. Wilson, Keith L. Ligon, Gordon Mills, Lewis C. Cantley, Lynda Chin

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere49466
JournalPLoS One
Volume7
Issue number11
DOIs
StatePublished - Nov 14 2012
Externally publishedYes

Fingerprint

somatic mutation
phosphatidylinositol 3-kinase
Glioblastoma
Phosphatidylinositols
Phosphotransferases
1-Phosphatidylinositol 4-Kinase
Mutation
neoplasms
Tumors
mutation
mutants
astrocytes
Heterografts
carcinogenesis
Genes
Neoplasms
Atlases
alleles
Molecules
genome

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Quayle, S. N., Lee, J. Y., Cheung, L. W. T., Ding, L., Wiedemeyer, R., Dewan, R. W., ... Chin, L. (2012). Somatic Mutations of PIK3R1 Promote Gliomagenesis. PLoS One, 7(11), [e49466]. https://doi.org/10.1371/journal.pone.0049466

Somatic Mutations of PIK3R1 Promote Gliomagenesis. / 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; Cantley, Lewis C.; Chin, Lynda.

In: PLoS One, Vol. 7, No. 11, e49466, 14.11.2012.

Research output: Contribution to journalArticle

Quayle, SN, Lee, JY, Cheung, LWT, Ding, L, Wiedemeyer, R, Dewan, RW, Huang-Hobbs, E, Zhuang, L, Wilson, RK, Ligon, KL, Mills, G, Cantley, LC & Chin, L 2012, 'Somatic Mutations of PIK3R1 Promote Gliomagenesis', PLoS One, vol. 7, no. 11, e49466. https://doi.org/10.1371/journal.pone.0049466
Quayle SN, Lee JY, Cheung LWT, Ding L, Wiedemeyer R, Dewan RW et al. Somatic Mutations of PIK3R1 Promote Gliomagenesis. PLoS One. 2012 Nov 14;7(11). e49466. https://doi.org/10.1371/journal.pone.0049466
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 ; Cantley, Lewis C. ; Chin, Lynda. / Somatic Mutations of PIK3R1 Promote Gliomagenesis. In: PLoS One. 2012 ; Vol. 7, No. 11.
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