Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas

Cancer Cell. 2020 Mar 16;37(3):308-323.e12. doi: 10.1016/j.ccell.2020.02.002. Epub 2020 Mar 5.

Abstract

Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors for which there is currently no effective treatment. Some of these tumors combine gain-of-function mutations in ACVR1, PIK3CA, and histone H3-encoding genes. The oncogenic mechanisms of action of ACVR1 mutations are currently unknown. Using mouse models, we demonstrate that Acvr1G328V arrests the differentiation of oligodendroglial lineage cells, and cooperates with Hist1h3bK27M and Pik3caH1047R to generate high-grade diffuse gliomas. Mechanistically, Acvr1G328V upregulates transcription factors which control differentiation and DIPG cell fitness. Furthermore, we characterize E6201 as a dual inhibitor of ACVR1 and MEK1/2, and demonstrate its efficacy toward tumor cells in vivo. Collectively, our results describe an oncogenic mechanism of action for ACVR1 mutations, and suggest therapeutic strategies for DIPGs.

Keywords: ACVR1; E6201; HIST1H3B; PIK3CA; bone morphogenetic protein; brain cancer; cancer therapeutic; diffuse intrinsic pontine glioma; glioma; oligodendrocyte.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / antagonists & inhibitors
  • Activin Receptors, Type I / chemistry*
  • Activin Receptors, Type I / genetics*
  • Activin Receptors, Type I / metabolism
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology*
  • Cell Differentiation / genetics
  • Cell Line, Tumor
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Class I Phosphatidylinositol 3-Kinases / metabolism
  • Female
  • Glioma / drug therapy
  • Glioma / genetics
  • Glioma / pathology*
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Lactones / pharmacology
  • Male
  • Mice, Transgenic
  • Mutation*
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / pathology
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Oligodendroglia / pathology
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • SOXC Transcription Factors / genetics
  • SOXC Transcription Factors / metabolism

Substances

  • 14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione
  • ASCL1 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Bone Morphogenetic Proteins
  • H3c2 protein, mouse
  • Histones
  • Lactones
  • SOX11 protein, human
  • SOXC Transcription Factors
  • Class I Phosphatidylinositol 3-Kinases
  • Pik3ca protein, mouse
  • Receptor, Platelet-Derived Growth Factor alpha
  • ACVR1 protein, human
  • Activin Receptors, Type I
  • Acvr1 protein, mouse