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

被引：0
|
作者：
Seneviratne, Janith A. [1 ,2 ]
Ravindrarajah, Daenikka [1 ,2 ]
Carter, Daniel R. [1 ,3 ]
Zhai, Vicki [1 ]
Lalwani, Amit [1 ]
Krishan, Sukriti [1 ,2 ]
Balachandran, Anushree [1 ]
Ng, Ernest [1 ,2 ]
Pandher, Ruby [1 ,2 ]
Wong, Matthew [1 ,2 ]
Nero, Tracy L. [4 ]
Wang, Shudong [5 ]
Norris, Murray D. [1 ,2 ,6 ]
Haber, Michelle [1 ,2 ]
Liu, Tao [1 ,2 ]
Parker, Michael W. [4 ,7 ]
Cheung, Belamy B. [1 ,2 ]
Marshall, Glenn M. [1 ,2 ,8 ]
机构：
[1] UNSW Sydney, Lowy Canc Res Ctr, Childrens Canc Inst Australia Med Res, Kensington, NSW, Australia
[2] UNSW Sydney, Fac Med & Hlth, Sch Clin Med, Kensington, NSW, Australia
[3] Univ Technol Sydney, Sch Biomed Engn, Sydney, NSW, Australia
[4] Univ Melbourne, Bio21 Mol Sci & Biotechnol Inst, Dept Biochem & Pharmacol, Parkville, Vic, Australia
[5] Univ South Australia, Ctr Drug Discovery & Dev, Clin & Hlth Sci, Adelaide, SA, Australia
[6] UNSW Sydney, Ctr Childhood Canc Res, Randwick, NSW, Australia
[7] St Vincents Inst Med Res, ACRF Rat Drug Discovery Ctr, Fitzroy, Vic, Australia
[8] Sydney Childrens Hosp, Kids Canc Ctr, Randwick, NSW, Australia
来源：
CANCER MEDICINE | 2024年 / 13卷 / 21期
关键词：
biomarkers; cancer biology; chromatin modifications and dynamics; epigenetics; molecular biology; neuroblastoma; INDUCED CELL-DEATH; N-MYC; CANCER-CELLS; RNA-SEQ; TRANSCRIPTION; ATF4; ENHANCER; GENE; CHEMOTHERAPY; METHYLATION;
D O I：
10.1002/cam4.70082
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
BackgroundThe 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.MethodsWe performed a high-throughput, combination chromatin-modifier drug screen against NB cells. We screened 13 drug candidates in 78 unique combinations.ResultsWe 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.ConclusionOur results support further investigation of HMT inhibitor combinations as a therapeutic approach in NB.
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页数：20
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