Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1016/j.ccell.2020.02.002

Type

Journal article

Journal

Cancer Cell

Publication Date

16/03/2020

Volume

37

Pages

308 - 323.e12

Keywords

ACVR1, E6201, HIST1H3B, PIK3CA, bone morphogenetic protein, brain cancer, cancer therapeutic, diffuse intrinsic pontine glioma, glioma, oligodendrocyte, Activin Receptors, Type I, Animals, Basic Helix-Loop-Helix Transcription Factors, Bone Morphogenetic Proteins, Brain Neoplasms, Cell Differentiation, Cell Line, Tumor, Class I Phosphatidylinositol 3-Kinases, Female, Glioma, Histones, Humans, Lactones, Male, Mice, Transgenic, Mutation, Neoplasms, Experimental, Neuroglia, Oligodendroglia, Receptor, Platelet-Derived Growth Factor alpha, SOXC Transcription Factors