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

被引:20
|
作者
Koncar, Robert F. [1 ,2 ]
Dey, Brittany R. [1 ,2 ,3 ]
Stanton, Ann-Catherine J. [1 ,2 ]
Agrawal, Nishant [1 ]
Wassell, Michelle L. [1 ,2 ]
McCarl, Lauren H. [1 ,2 ]
Locke, Abigail. L. [1 ]
Sanders, Lauren [4 ]
Morozova-Vaske, Olena [4 ,5 ]
Myers, Max I. [1 ]
Hamilton, Ronald L. [6 ]
Carcaboso, Angel M. [7 ]
Kohanbash, Gary [1 ,2 ]
Hu, Baoli [1 ,2 ]
Amankulor, Nduka M. [2 ]
Felker, James [8 ]
Kambhampati, Madhuri [9 ,10 ]
Nazarian, Javad [9 ,10 ,11 ]
Becher, Oren J. [12 ,13 ]
James, C. David [13 ,14 ,15 ]
Hashizume, Rintaro [13 ,14 ,15 ]
Broniscer, Alberto [8 ]
Pollack, Ian F. [1 ,2 ]
Agnihotri, Sameer [1 ,2 ,16 ]
机构
[1] Childrens Hosp Pittsburgh, John G Rangos Sr Res Ctr, Pittsburgh, PA 15213 USA
[2] Univ Pittsburgh, Sch Med, Dept Neurol Surg, Pittsburgh, PA 15261 USA
[3] Suny Downstate Med Ctr, New York, NY USA
[4] Univ Calif Santa Cruz, Dept Mol Cell & Dev Biol, Santa Cruz, CA 95064 USA
[5] Univ Calif Santa Cruz, Genom Inst, Santa Cruz, CA 95064 USA
[6] Univ Pittsburgh, Canc Inst, Dept Pathol, Pittsburgh, PA USA
[7] Inst Recerca St Joan Deu, Barcelona, Spain
[8] UPMC Childrens Hosp Pittsburgh, Pediat Neurooncol Program, Pittsburgh, PA USA
[9] Childrens Natl Hlth Syst, Washington, DC USA
[10] George Washington Univ, Sch Med & Hlth Sci, Dept Genom & Precis Med, Washington, DC 20052 USA
[11] Univ Childrens Hosp Zurich, Dept Oncol, Zurich, Switzerland
[12] Ann & Robert H Lurie Childrens Hosp Chicago, Div Hematol Oncol & Stem Cell Transplant, Chicago, IL 60611 USA
[13] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Canc Ctr, Dept Biochem & Mol Genet, Chicago, IL 60611 USA
[14] Northwestern Univ, Robert H Lurie NCI Comprehens Canc Ctr, Dept Neurol Surg, Chicago, IL 60611 USA
[15] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA
[16] Univ Pittsburgh, Dept Neurobiol, Pittsburgh, PA USA
关键词
PEDIATRIC HIGH-GRADE; HISTONE H3.3; BRAIN; INHIBITION; EXPRESSION; MUTATIONS; SUBGROUPS; DORMANCY; TARGET; GENES;
D O I
10.1158/0008-5472.CAN-18-3521
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:4026 / 4041
页数:16
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