Combined inhibition of histone methyltransferases EZH2 and DOT1L is an effective therapy for neuroblastoma.

Seneviratne, JA; Ravindrarajah, D; Carter, DR; Zhai, V; Lalwani, A; Krishan, S; Balachandran, A; Ng, E; Pandher, R; Wong, M; Nero, TL; Wang, S; Norris, MD; Haber, M; Liu, T; Parker, MW; Cheung, BB; Marshall, GM

Combined inhibition of histone methyltransferases EZH2 and DOT1L is an effective therapy for neuroblastoma.

Seneviratne, JA Ravindrarajah, D Carter, DR Zhai, V Lalwani, A Krishan, S Balachandran, A Ng, E Pandher, R Wong, M Nero, TL Wang, S Norris, MD Haber, M Liu, T Parker, MW Cheung, BB Marshall, GM

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Publisher:: Wiley
Publication Type:: Journal Article
Citation:: Cancer Med, 2024, 13, (21), pp. e70082
Issue Date:: 2024-11

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Field	Value	Language
dc.contributor.author	Seneviratne, JA
dc.contributor.author	Ravindrarajah, D
dc.contributor.author	Carter, DR
dc.contributor.author	Zhai, V
dc.contributor.author	Lalwani, A
dc.contributor.author	Krishan, S
dc.contributor.author	Balachandran, A
dc.contributor.author	Ng, E
dc.contributor.author	Pandher, R
dc.contributor.author	Wong, M
dc.contributor.author	Nero, TL
dc.contributor.author	Wang, S
dc.contributor.author	Norris, MD
dc.contributor.author	Haber, M
dc.contributor.author	Liu, T
dc.contributor.author	Parker, MW
dc.contributor.author	Cheung, BB
dc.contributor.author	Marshall, GM
dc.date.accessioned	2025-01-28T05:05:54Z
dc.date.available	2024-07-24
dc.date.available	2025-01-28T05:05:54Z
dc.date.issued	2024-11
dc.identifier.citation	Cancer Med, 2024, 13, (21), pp. e70082
dc.identifier.issn	2045-7634
dc.identifier.issn	2045-7634
dc.identifier.uri	http://hdl.handle.net/10453/184275
dc.description.abstract	BACKGROUND: The child cancer, neuroblastoma (NB), is characterised by a low incidence of mutations and strong oncogenic embryonal driver signals. Many new targeted epigenetic modifier drugs have failed in human trials as monotherapy. METHODS: We performed a high-throughput, combination chromatin-modifier drug screen against NB cells. We screened 13 drug candidates in 78 unique combinations. RESULTS: We found that the combination of two histone methyltransferase (HMT) inhibitors: GSK343, targeting EZH2, and SGC0946, targeting DOT1L, demonstrated the strongest synergy across 8 NB cell lines, with low normal fibroblast toxicity. High mRNA expression of both EZH2 and DOT1L in NB tumour samples correlated with the poorest patient survival. Combination HMT inhibitor treatment caused activation of ATF4-mediated endoplasmic reticulum (ER) stress responses. In addition, glutathione and several amino acids were depleted by HMT inhibitor combination on mass spectrometry analysis. The combination of SGC0946 and GSK343 reduced tumour growth in comparison to single agents. CONCLUSION: Our results support further investigation of HMT inhibitor combinations as a therapeutic approach in NB.
dc.format	Print
dc.language	eng
dc.publisher	Wiley
dc.relation.ispartof	Cancer Med
dc.relation.isbasedon	10.1002/cam4.70082
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0601 Biochemistry and Cell Biology, 1112 Oncology and Carcinogenesis
dc.subject.classification	3211 Oncology and carcinogenesis
dc.subject.mesh	Humans
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Enhancer of Zeste Homolog 2 Protein
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Histone-Lysine N-Methyltransferase
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Endoplasmic Reticulum Stress
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	Antineoplastic Combined Chemotherapy Protocols
dc.subject.mesh	Activating Transcription Factor 4
dc.subject.mesh	Drug Synergism
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.subject.mesh	Enzyme Inhibitors
dc.subject.mesh	Indazoles
dc.subject.mesh	Pyridones
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Indazoles
dc.subject.mesh	Pyridones
dc.subject.mesh	Histone-Lysine N-Methyltransferase
dc.subject.mesh	Antineoplastic Combined Chemotherapy Protocols
dc.subject.mesh	Enzyme Inhibitors
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	Drug Synergism
dc.subject.mesh	Activating Transcription Factor 4
dc.subject.mesh	Endoplasmic Reticulum Stress
dc.subject.mesh	Enhancer of Zeste Homolog 2 Protein
dc.subject.mesh	Humans
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Enhancer of Zeste Homolog 2 Protein
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Histone-Lysine N-Methyltransferase
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Endoplasmic Reticulum Stress
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	Antineoplastic Combined Chemotherapy Protocols
dc.subject.mesh	Activating Transcription Factor 4
dc.subject.mesh	Drug Synergism
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.subject.mesh	Enzyme Inhibitors
dc.subject.mesh	Indazoles
dc.subject.mesh	Pyridones
dc.title	Combined inhibition of histone methyltransferases EZH2 and DOT1L is an effective therapy for neuroblastoma.
dc.type	Journal Article
utslib.citation.volume	13
utslib.location.activity	United States
utslib.for	0601 Biochemistry and Cell Biology
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	University of Technology Sydney/UTS Groups
pubs.organisational-group	University of Technology Sydney/UTS Groups/Centre for Health Technologies (CHT)
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2025-01-28T05:05:49Z
pubs.issue	21
pubs.publication-status	Published
pubs.volume	13
utslib.citation.issue	21

Abstract:

BACKGROUND: The child cancer, neuroblastoma (NB), is characterised by a low incidence of mutations and strong oncogenic embryonal driver signals. Many new targeted epigenetic modifier drugs have failed in human trials as monotherapy. METHODS: We performed a high-throughput, combination chromatin-modifier drug screen against NB cells. We screened 13 drug candidates in 78 unique combinations. RESULTS: We found that the combination of two histone methyltransferase (HMT) inhibitors: GSK343, targeting EZH2, and SGC0946, targeting DOT1L, demonstrated the strongest synergy across 8 NB cell lines, with low normal fibroblast toxicity. High mRNA expression of both EZH2 and DOT1L in NB tumour samples correlated with the poorest patient survival. Combination HMT inhibitor treatment caused activation of ATF4-mediated endoplasmic reticulum (ER) stress responses. In addition, glutathione and several amino acids were depleted by HMT inhibitor combination on mass spectrometry analysis. The combination of SGC0946 and GSK343 reduced tumour growth in comparison to single agents. CONCLUSION: Our results support further investigation of HMT inhibitor combinations as a therapeutic approach in NB.

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http://hdl.handle.net/10453/184275