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| Status |
Public on Nov 13, 2024 |
| Title |
Combined inhibition of histone methyltransferases EZH2 and DOT1L is an effective therapy for neuroblastoma |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
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. We performed a high‐throughput, combination chromatin‐modifier drug screen against NB cells. We screened 13 drug candidates in 78 unique combinations. 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. Our results support further investigation of HMT inhibitor combinations as a therapeutic approach in NB.
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| Overall design |
SK‐N‐BE(2)‐C and KELLY neuroblastoma cell lines were seeded in T25 flasks. Following 24 h of incubation cell culture medium was replaced with medium containing either DMSO, 12.8 μM SGC0946, 12.8 μM GSK343 or a combination of both drugs. Treated cells were incubated for 6 h, followed by total RNA extraction and quantitation. RNA from treated samples were then subject to microarray profiling via the PrimeView Human Genome U219 Array (#901605 Applied Biosystems) according to manufacturer instructions, by the Ramaciotti Centre for Genomics (UNSW, Australia).
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| Contributor(s) |
Seneviratne JA |
| Citation(s) |
39501501 |
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| Submission date |
Nov 13, 2024 |
| Last update date |
Nov 14, 2024 |
| Contact name |
Janith Seneviratne |
| E-mail(s) |
[email protected]
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| Organization name |
Peter MacCallum Cancer Centre
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| Lab |
Eckersley-Maslin
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| Street address |
Peter MacCallum Cancer Centre, 305 Grattan Street
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| City |
Melbourne |
| State/province |
VIC |
| ZIP/Postal code |
3000 |
| Country |
Australia |
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| Platforms (1) |
| GPL13667 |
[HG-U219] Affymetrix Human Genome U219 Array |
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| Samples (16)
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| Relations |
| BioProject |
PRJNA1185740 |
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