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Somatic mutations of PIK3R1 promote gliomagenesis

Steven N Quayle1, Jennifer Y Lee, Lydia W T Cheung

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Plos One
|November 21, 2012
PubMed

Insights

Mutations in PIK3R1 drive glioblastoma (GBM) by activating the PI3K pathway. Targeting AKT may benefit GBM patients with these specific PIK3R1 mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • The phosphoinositide 3-kinase (PI3K) pathway is frequently altered in glioblastoma (GBM).
  • PIK3R1 somatic mutations are found in various tumors, but their role in GBM tumorigenesis is unclear.

Purpose of the Study:

  • To investigate the oncogenic role of PIK3R1 mutations in glioblastoma.
  • To determine if PIK3R1 mutations promote GBM development and if they sensitize cells to targeted therapies.

Main Methods:

  • Introducing specific PIK3R1 mutations (nSH2 and iSH2 domains) into normal human astrocytes.
  • Assessing PI3K pathway signaling and tumor formation in an orthotopic xenograft model.
  • Evaluating the sensitivity of cells with mutant PIK3R1 to AKT inhibitors.

Main Results:

  • Somatic mutations in the iSH2 domain of PIK3R1 act as oncogenic drivers in GBM.
  • Specific PIK3R1 mutations increase PI3K pathway signaling and promote astrocyte tumorigenesis.
  • Cells dependent on mutant P85α PI3K signaling show enhanced sensitivity to AKT inhibitors.

Conclusions:

  • PIK3R1 mutations are oncogenic drivers in glioblastoma.
  • Targeting AKT signaling represents a potential therapeutic strategy for GBM patients with mutant PIK3R1.

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