Combined inhibition of histone methyltransferases EZH2 and DOT1L is an effective therapy for neuroblastoma.
| Title: | Combined inhibition of histone methyltransferases EZH2 and DOT1L is an effective therapy for neuroblastoma. |
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| Authors: | Seneviratne, Janith A., Ravindrarajah, Daenikka, Carter, Daniel R., Zhai, Vicki, Lalwani, Amit, Krishan, Sukriti, Balachandran, Anushree, Ng, Ernest, Pandher, Ruby, Wong, Matthew, Nero, Tracy L., Wang, Shudong, Norris, Murray D., Haber, Michelle, Liu, Tao, Parker, Michael W., Cheung, Belamy B., Marshall, Glenn M. |
| Source: | Cancer Medicine; Nov2024, Vol. 13 Issue 21, p1-20, 20p |
| Subject Terms: | MOLECULAR biology, HISTONE methyltransferases, GENE expression, ENDOPLASMIC reticulum, TUMOR markers, NEUROBLASTOMA |
| 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. [ABSTRACT FROM AUTHOR] |
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| Database: | Complementary Index |
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| Items | – Name: Title Label: Title Group: Ti Data: Combined inhibition of histone methyltransferases EZH2 and DOT1L is an effective therapy for neuroblastoma. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Seneviratne%2C+Janith+A%2E%22">Seneviratne, Janith A.</searchLink><br /><searchLink fieldCode="AR" term="%22Ravindrarajah%2C+Daenikka%22">Ravindrarajah, Daenikka</searchLink><br /><searchLink fieldCode="AR" term="%22Carter%2C+Daniel+R%2E%22">Carter, Daniel R.</searchLink><br /><searchLink fieldCode="AR" term="%22Zhai%2C+Vicki%22">Zhai, Vicki</searchLink><br /><searchLink fieldCode="AR" term="%22Lalwani%2C+Amit%22">Lalwani, Amit</searchLink><br /><searchLink fieldCode="AR" term="%22Krishan%2C+Sukriti%22">Krishan, Sukriti</searchLink><br /><searchLink fieldCode="AR" term="%22Balachandran%2C+Anushree%22">Balachandran, Anushree</searchLink><br /><searchLink fieldCode="AR" term="%22Ng%2C+Ernest%22">Ng, Ernest</searchLink><br /><searchLink fieldCode="AR" term="%22Pandher%2C+Ruby%22">Pandher, Ruby</searchLink><br /><searchLink fieldCode="AR" term="%22Wong%2C+Matthew%22">Wong, Matthew</searchLink><br /><searchLink fieldCode="AR" term="%22Nero%2C+Tracy+L%2E%22">Nero, Tracy L.</searchLink><br /><searchLink fieldCode="AR" term="%22Wang%2C+Shudong%22">Wang, Shudong</searchLink><br /><searchLink fieldCode="AR" term="%22Norris%2C+Murray+D%2E%22">Norris, Murray D.</searchLink><br /><searchLink fieldCode="AR" term="%22Haber%2C+Michelle%22">Haber, Michelle</searchLink><br /><searchLink fieldCode="AR" term="%22Liu%2C+Tao%22">Liu, Tao</searchLink><br /><searchLink fieldCode="AR" term="%22Parker%2C+Michael+W%2E%22">Parker, Michael W.</searchLink><br /><searchLink fieldCode="AR" term="%22Cheung%2C+Belamy+B%2E%22">Cheung, Belamy B.</searchLink><br /><searchLink fieldCode="AR" term="%22Marshall%2C+Glenn+M%2E%22">Marshall, Glenn M.</searchLink> – Name: TitleSource Label: Source Group: Src Data: Cancer Medicine; Nov2024, Vol. 13 Issue 21, p1-20, 20p – Name: Subject Label: Subject Terms Group: Su Data: <searchLink fieldCode="DE" term="%22MOLECULAR+biology%22">MOLECULAR biology</searchLink><br /><searchLink fieldCode="DE" term="%22HISTONE+methyltransferases%22">HISTONE methyltransferases</searchLink><br /><searchLink fieldCode="DE" term="%22GENE+expression%22">GENE expression</searchLink><br /><searchLink fieldCode="DE" term="%22ENDOPLASMIC+reticulum%22">ENDOPLASMIC reticulum</searchLink><br /><searchLink fieldCode="DE" term="%22TUMOR+markers%22">TUMOR markers</searchLink><br /><searchLink fieldCode="DE" term="%22NEUROBLASTOMA%22">NEUROBLASTOMA</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: 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. [ABSTRACT FROM AUTHOR] – Name: Abstract Label: Group: Ab Data: <i>Copyright of Cancer Medicine is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1002/cam4.70082 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 20 StartPage: 1 Subjects: – SubjectFull: MOLECULAR biology Type: general – SubjectFull: HISTONE methyltransferases Type: general – SubjectFull: GENE expression Type: general – SubjectFull: ENDOPLASMIC reticulum Type: general – SubjectFull: TUMOR markers Type: general – SubjectFull: NEUROBLASTOMA Type: general Titles: – TitleFull: Combined inhibition of histone methyltransferases EZH2 and DOT1L is an effective therapy for neuroblastoma. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Seneviratne, Janith A. – PersonEntity: Name: NameFull: Ravindrarajah, Daenikka – PersonEntity: Name: NameFull: Carter, Daniel R. – PersonEntity: Name: NameFull: Zhai, Vicki – PersonEntity: Name: NameFull: Lalwani, Amit – PersonEntity: Name: NameFull: Krishan, Sukriti – PersonEntity: Name: NameFull: Balachandran, Anushree – PersonEntity: Name: NameFull: Ng, Ernest – PersonEntity: Name: NameFull: Pandher, Ruby – PersonEntity: Name: NameFull: Wong, Matthew – PersonEntity: Name: NameFull: Nero, Tracy L. – PersonEntity: Name: NameFull: Wang, Shudong – PersonEntity: Name: NameFull: Norris, Murray D. – PersonEntity: Name: NameFull: Haber, Michelle – PersonEntity: Name: NameFull: Liu, Tao – PersonEntity: Name: NameFull: Parker, Michael W. – PersonEntity: Name: NameFull: Cheung, Belamy B. – PersonEntity: Name: NameFull: Marshall, Glenn M. IsPartOfRelationships: – BibEntity: Dates: – D: 01 M: 11 Text: Nov2024 Type: published Y: 2024 Identifiers: – Type: issn-print Value: 20457634 Numbering: – Type: volume Value: 13 – Type: issue Value: 21 Titles: – TitleFull: Cancer Medicine Type: main |
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