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

• Published in: Cancer cell 2017-12, Vol.32 (6), p.856-868.e5
• Main Authors: Cosset, Érika, Ilmjärv, Sten, Dutoit, Valérie, Elliott, Kathryn, von Schalscha, Tami, Camargo, Maria F., Reiss, Alexander, Moroishi, Toshiro, Seguin, Laetitia, Gomez, German, Moo, Jung-Soon, Preynat-Seauve, Olivier, Krause, Karl-Heinz, Chneiweiss, Hervé, Sarkaria, Jann N., Guan, Kun-Liang, Dietrich, Pierre-Yves, Weis, Sara M., Mischel, Paul S., Cheresh, David A.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Brain Neoplasms - metabolism; Brain Neoplasms - mortality; cancer stem cells; Cell Line, Tumor; Gene Expression Profiling; glioblastoma; Glioblastoma - metabolism; Glioblastoma - mortality; glucose metabolism; Glucose Transporter Type 3 - metabolism; Glut3; Humans; integrin; Integrin alphaVbeta3 - metabolism; Kaplan-Meier Estimate; Life Sciences; Mice; Mice, Nude; Signal Transduction; Snake Venoms - pharmacology; Transcriptome; Xenograft Model Antitumor Assays
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2017.10.016

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. [Display omitted] •High expression of integrin β3 is associated with shorter survival for gliomas•Integrin αvβ3 drives Glut3 expression through PAK4/YAP/TAZ•Genetic signature predicts Glut3 addiction for a subset of classical/proneural GBM•Glut3-addicted tumors are highly sensitive to agents targeting αvβ3 Cosset et al. identify a subset of glioblastoma within the proneural and the classical subtypes that are addicted to aberrant signaling from integrin αvβ3, which activates a PAK4-YAP/TAZ signaling axis to enhance Glut3 expression, and are sensitive to agents disrupting the pathway such as cilengitide.