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 Josh Becher, Charles David James & 4 others Rintaro Hashizume, Alberto Broniscer, Ian F. Pollack, Sameer Agnihotri*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

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
Volume79
Issue number16
DOIs
StatePublished - Aug 15 2019

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Glioma
Mutation
Therapeutics
Brain Stem Neoplasms
Proto-Oncogenes
Receptor Protein-Tyrosine Kinases
Brain Neoplasms
Histones
Proteins
Cell Proliferation
Apoptosis
Survival
Growth
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Koncar, R. F., Dey, B. R., Stanton, A. C. J., Agrawal, N., Wassell, M. L., McCarl, L. H., ... Agnihotri, S. (2019). Identification of novel Ras signaling therapeutic vulnerabilities in diffuse intrinsic pontine gliomas. Cancer Research, 79(16), 4026-4041. https://doi.org/10.1158/0008-5472.CAN-18-3521
Koncar, Robert F. ; Dey, Brittany R. ; Stanton, Ann Catherine J. ; Agrawal, Nishant ; Wassell, Michelle L. ; McCarl, Lauren H. ; Locke, Abigail L. ; Sanders, Lauren ; Morozova-Vaske, Olena ; Myers, Max I. ; Hamilton, Ronald L. ; Carcaboso, Angel M. ; Kohanbash, Gary ; Hu, Baoli ; Amankulor, Nduka M. ; Felker, James ; Kambhampati, Madhuri ; Nazarian, Javad ; Becher, Oren Josh ; James, Charles David ; Hashizume, Rintaro ; Broniscer, Alberto ; Pollack, Ian F. ; Agnihotri, Sameer. / Identification of novel Ras signaling therapeutic vulnerabilities in diffuse intrinsic pontine gliomas. In: Cancer Research. 2019 ; Vol. 79, No. 16. pp. 4026-4041.
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abstract = "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.",
author = "Koncar, {Robert F.} and Dey, {Brittany R.} and Stanton, {Ann Catherine J.} and Nishant Agrawal and Wassell, {Michelle L.} and McCarl, {Lauren H.} and Locke, {Abigail L.} and Lauren Sanders and Olena Morozova-Vaske and Myers, {Max I.} and Hamilton, {Ronald L.} and Carcaboso, {Angel M.} and Gary Kohanbash and Baoli Hu and Amankulor, {Nduka M.} and James Felker and Madhuri Kambhampati and Javad Nazarian and Becher, {Oren Josh} and James, {Charles David} and Rintaro Hashizume and Alberto Broniscer and Pollack, {Ian F.} and Sameer Agnihotri",
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Koncar, RF, Dey, BR, Stanton, ACJ, Agrawal, N, Wassell, ML, McCarl, LH, Locke, AL, Sanders, L, Morozova-Vaske, O, Myers, MI, Hamilton, RL, Carcaboso, AM, Kohanbash, G, Hu, B, Amankulor, NM, Felker, J, Kambhampati, M, Nazarian, J, Becher, OJ, James, CD, Hashizume, R, Broniscer, A, Pollack, IF & Agnihotri, S 2019, 'Identification of novel Ras signaling therapeutic vulnerabilities in diffuse intrinsic pontine gliomas', Cancer Research, vol. 79, no. 16, pp. 4026-4041. https://doi.org/10.1158/0008-5472.CAN-18-3521

Identification of novel Ras signaling therapeutic vulnerabilities in diffuse intrinsic pontine gliomas. / Koncar, Robert F.; Dey, Brittany R.; Stanton, Ann Catherine J.; Agrawal, Nishant; Wassell, Michelle L.; McCarl, Lauren H.; Locke, Abigail L.; Sanders, Lauren; Morozova-Vaske, Olena; Myers, Max I.; Hamilton, Ronald L.; Carcaboso, Angel M.; Kohanbash, Gary; Hu, Baoli; Amankulor, Nduka M.; Felker, James; Kambhampati, Madhuri; Nazarian, Javad; Becher, Oren Josh; James, Charles David; Hashizume, Rintaro; Broniscer, Alberto; Pollack, Ian F.; Agnihotri, Sameer.

In: Cancer Research, Vol. 79, No. 16, 15.08.2019, p. 4026-4041.

Research output: Contribution to journalArticle

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T1 - Identification of novel Ras signaling therapeutic vulnerabilities in diffuse intrinsic pontine gliomas

AU - Koncar, Robert F.

AU - Dey, Brittany R.

AU - Stanton, Ann Catherine J.

AU - Agrawal, Nishant

AU - Wassell, Michelle L.

AU - McCarl, Lauren H.

AU - Locke, Abigail L.

AU - Sanders, Lauren

AU - Morozova-Vaske, Olena

AU - Myers, Max I.

AU - Hamilton, Ronald L.

AU - Carcaboso, Angel M.

AU - Kohanbash, Gary

AU - Hu, Baoli

AU - Amankulor, Nduka M.

AU - Felker, James

AU - Kambhampati, Madhuri

AU - Nazarian, Javad

AU - Becher, Oren Josh

AU - James, Charles David

AU - Hashizume, Rintaro

AU - Broniscer, Alberto

AU - Pollack, Ian F.

AU - Agnihotri, Sameer

PY - 2019/8/15

Y1 - 2019/8/15

N2 - 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.

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