Journal
PLOS ONE
Volume 7, Issue 11, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0049466
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Funding
- CIHR Funding Source: Medline
- NCI NIH HHS [P01CA095616, RC2CA148268, U01CA141508, P01 CA095616, U01 CA168394, P50 CA098258, U01CA168394, P30 CA016672, U24CA143845, RC2 CA148268, U24 CA143845, U01 CA141508] Funding Source: Medline
- NIGMS NIH HHS [R01 GM041890] Funding Source: Medline
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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 P85 alpha-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.
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