Glut3 Addiction Is a Druggable Vulnerability for a Molecularly Defined Subpopulation of Glioblastoma

Cancer Cell. 2017 Dec 11;32(6):856-868.e5. doi: 10.1016/j.ccell.2017.10.016. Epub 2017 Nov 30.

Abstract

While molecular subtypes of glioblastoma (GBM) are defined using gene expression and mutation profiles, we identify a unique subpopulation based on addiction to the high-affinity glucose transporter, Glut3. Although Glut3 is a known driver of a cancer stem cell phenotype, direct targeting is complicated by its expression in neurons. Using established GBM lines and patient-derived stem cells, we identify a subset of tumors within the "proneural" and "classical" subtypes that are addicted to aberrant signaling from integrin αvβ3, which activates a PAK4-YAP/TAZ signaling axis to enhance Glut3 expression. This defined subpopulation of GBM is highly sensitive to agents that disrupt this pathway, including the integrin antagonist cilengitide, providing a targeted therapeutic strategy for this unique subset of GBM tumors.

Keywords: Glut3; cancer stem cells; glioblastoma; glucose metabolism; integrin.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / mortality
  • Cell Line, Tumor
  • Gene Expression Profiling
  • Glioblastoma / metabolism*
  • Glioblastoma / mortality
  • Glucose Transporter Type 3 / metabolism*
  • Humans
  • Integrin alphaVbeta3 / metabolism*
  • Kaplan-Meier Estimate
  • Mice
  • Mice, Nude
  • Signal Transduction
  • Snake Venoms / pharmacology
  • Transcriptome*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Glucose Transporter Type 3
  • Integrin alphaVbeta3
  • SLC2A3 protein, human
  • Snake Venoms
  • Cilengitide