Identification of novel Ras signaling therapeutic vulnerabilities in diffuse intrinsic pontine gliomas

Robert F. Koncar, Brittany R. Dey, Ann Catherine J. Stanton, Nishant Agrawal, Michelle L. Wassell, Lauren H. McCarl, Abigail L. Locke, Lauren Sanders, Olena Morozova-Vaske, Max I. Myers, Ronald L. Hamilton, Angel M. Carcaboso, Gary Kohanbash, Baoli Hu, Nduka M. Amankulor, James Felker, Madhuri Kambhampati, Javad Nazarian, Oren J. Becher, C. David JamesRintaro Hashizume, Alberto Broniscer, Ian F. Pollack, Sameer Agnihotri*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Diffuse intrinsic pontine gliomas (DIPG) are incurable brain tumors with an aggressive onset. Apart from irradiation, there are currently no effective therapies available for patients with DIPG, who have a median survival time of less than one year. Most DIPG cells harbor mutations in genes encoding histone H3 (H3K27M) proteins, resulting in a global reduction of H3K27 trimethylation and activation of oncogenic signaling pathways. Here we show that the H3K27M mutations contribute to RAS pathway signaling, which is augmented by additional RAS activators including PDGFRA. H3K27M mutation led to increased expression of receptor tyrosine kinases (RTK). A RAS pathway functional screen identified ERK5, but not ERK1/2, as a RAS pathway effector important for DIPG growth. Suppression of ERK5 decreased DIPG cell proliferation and induced apoptosis in vitro and in vivo. In addition, depletion or inhibition of ERK5 significantly increased survival of mice intracranially engrafted with DIPG cells. Mechanistically, ERK5 directly stabilized the proto-oncogene MYC at the protein level. Collectively, our data demonstrate an underappreciated role of H3K27M in RAS activation and reveal novel therapeutic targets for treating DIPG tumors.

Original languageEnglish (US)
Pages (from-to)4026-4041
Number of pages16
JournalCancer Research
Issue number16
StatePublished - Aug 15 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'Identification of novel Ras signaling therapeutic vulnerabilities in diffuse intrinsic pontine gliomas'. Together they form a unique fingerprint.

Cite this