Identification of Novel RAS Signaling Therapeutic Vulnerabilities in Diffuse Intrinsic Pontine Gliomas.

Autor:	Koncar RF; John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.; Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Dey BR; John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.; Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; SUNY Downstate Medical Center, New York, New York., Stanton AJ; John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.; Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Agrawal N; John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania., Wassell ML; John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.; Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., McCarl LH; John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.; Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Locke AL; John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania., Sanders L; Department of Molecular, Cell, and Developmental Biology, University of California Santa Cruz, Santa Cruz, California., Morozova-Vaske O; Department of Molecular, Cell, and Developmental Biology, University of California Santa Cruz, Santa Cruz, California.; University of California Santa Cruz Genomics Institute, Santa Cruz, California., Myers MI; John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania., Hamilton RL; Department of Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania., Carcaboso AM; Institut de Recerca Sant Joan de Deu, Barcelona, Spain., Kohanbash G; John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.; Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Hu B; John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.; Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Amankulor NM; Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Felker J; Pediatric Neuro-Oncology Program, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania., Kambhampati M; Children's National Health System, Washington, D.C.; Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, D.C., Nazarian J; Children's National Health System, Washington, D.C.; Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, D.C.; Department of Oncology, University Children's Hospital Zürich, Zürich, Switzerland., Becher OJ; Division of Hematology, Oncology and Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.; Department of Biochemistry and Molecular Genetics, Robert H. Lurie Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois., James CD; Department of Biochemistry and Molecular Genetics, Robert H. Lurie Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.; Department of Neurological Surgery, Robert H. Lurie NCI Comprehensive Cancer Center, Northwestern University, Chicago, Illinois.; Feinberg School of Medicine, Northwestern University, Chicago, Illinois., Hashizume R; Department of Biochemistry and Molecular Genetics, Robert H. Lurie Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.; Department of Neurological Surgery, Robert H. Lurie NCI Comprehensive Cancer Center, Northwestern University, Chicago, Illinois.; Feinberg School of Medicine, Northwestern University, Chicago, Illinois., Broniscer A; Pediatric Neuro-Oncology Program, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania., Pollack IF; John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.; Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Agnihotri S; John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania. sameer.agnihotri@pitt.edu.; Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2019 Aug 15; Vol. 79 (16), pp. 4026-4041. Date of Electronic Publication: 2019 Jun 14.
DOI:	10.1158/0008-5472.CAN-18-3521
Abstrakt:	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. SIGNIFICANCE: These findings identify the H3K27M mutation as an enhancer of RAS activation in DIPG and ERK5 as a novel, immediately actionable molecular target. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/16/4026/F1.large.jpg. (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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