PRMT5 inhibition shows in vitro efficacy against H3K27M-altered diffuse midline glioma, but does not extend survival in vivo
Abstract H3K27-altered Diffuse Midline Glioma (DMG) is a universally fatal paediatric brainstem tumour. The prevalent driver mutation H3K27M creates a unique epigenetic landscape that may also establish therapeutic vulnerabilities to epigenetic inhibitors. However, while HDAC, EZH2 and BET inhibitor...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-48652-x |
| _version_ | 1797363396807491584 |
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| author | Elizabeth J. Brown Leire Balaguer-Lluna Adam P. Cribbs Martin Philpott Leticia Campo Molly Browne Jong Fu Wong Udo Oppermann Ángel M. Carcaboso Alex N. Bullock Gillian Farnie |
| author_facet | Elizabeth J. Brown Leire Balaguer-Lluna Adam P. Cribbs Martin Philpott Leticia Campo Molly Browne Jong Fu Wong Udo Oppermann Ángel M. Carcaboso Alex N. Bullock Gillian Farnie |
| author_sort | Elizabeth J. Brown |
| collection | DOAJ |
| description | Abstract H3K27-altered Diffuse Midline Glioma (DMG) is a universally fatal paediatric brainstem tumour. The prevalent driver mutation H3K27M creates a unique epigenetic landscape that may also establish therapeutic vulnerabilities to epigenetic inhibitors. However, while HDAC, EZH2 and BET inhibitors have proven somewhat effective in pre-clinical models, none have translated into clinical benefit due to either poor blood–brain barrier penetration, lack of efficacy or toxicity. Thus, there remains an urgent need for new DMG treatments. Here, we performed wider screening of an epigenetic inhibitor library and identified inhibitors of protein arginine methyltransferases (PRMTs) among the top hits reducing DMG cell viability. Two of the most effective inhibitors, LLY-283 and GSK591, were targeted against PRMT5 using distinct binding mechanisms and reduced the viability of a subset of DMG cells expressing wild-type TP53 and mutant ACVR1. RNA-sequencing and phenotypic analyses revealed that LLY-283 could reduce the viability, clonogenicity and invasion of DMG cells in vitro, representing three clinically important phenotypes, but failed to prolong survival in an orthotopic xenograft model. Together, these data show the challenges of DMG treatment and highlight PRMT5 inhibitors for consideration in future studies of combination treatments. |
| first_indexed | 2024-03-08T16:20:48Z |
| format | Article |
| id | doaj.art-cd300eaf757540c2bae8198462204942 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-08T16:20:48Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-cd300eaf757540c2bae81984622049422024-01-07T12:22:47ZengNature PortfolioScientific Reports2045-23222024-01-0114111710.1038/s41598-023-48652-xPRMT5 inhibition shows in vitro efficacy against H3K27M-altered diffuse midline glioma, but does not extend survival in vivoElizabeth J. Brown0Leire Balaguer-Lluna1Adam P. Cribbs2Martin Philpott3Leticia Campo4Molly Browne5Jong Fu Wong6Udo Oppermann7Ángel M. Carcaboso8Alex N. Bullock9Gillian Farnie10Nuffield Department of Medicine, Centre for Medicines Discovery, University of OxfordSJD Pediatric Cancer Center Barcelona, Hospital Sant Joan de Deu, Institut de Recerca Sant Joan de DeuNuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, National Institute of Health Research Oxford Biomedical Research Unit (BRU), University of OxfordNuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, National Institute of Health Research Oxford Biomedical Research Unit (BRU), University of OxfordDepartment of Oncology, Experimental Cancer Medicine Centre, University of OxfordDepartment of Oncology, Experimental Cancer Medicine Centre, University of OxfordNuffield Department of Medicine, Centre for Medicines Discovery, University of OxfordNuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, National Institute of Health Research Oxford Biomedical Research Unit (BRU), University of OxfordSJD Pediatric Cancer Center Barcelona, Hospital Sant Joan de Deu, Institut de Recerca Sant Joan de DeuNuffield Department of Medicine, Centre for Medicines Discovery, University of OxfordNuffield Department of Medicine, Centre for Medicines Discovery, University of OxfordAbstract H3K27-altered Diffuse Midline Glioma (DMG) is a universally fatal paediatric brainstem tumour. The prevalent driver mutation H3K27M creates a unique epigenetic landscape that may also establish therapeutic vulnerabilities to epigenetic inhibitors. However, while HDAC, EZH2 and BET inhibitors have proven somewhat effective in pre-clinical models, none have translated into clinical benefit due to either poor blood–brain barrier penetration, lack of efficacy or toxicity. Thus, there remains an urgent need for new DMG treatments. Here, we performed wider screening of an epigenetic inhibitor library and identified inhibitors of protein arginine methyltransferases (PRMTs) among the top hits reducing DMG cell viability. Two of the most effective inhibitors, LLY-283 and GSK591, were targeted against PRMT5 using distinct binding mechanisms and reduced the viability of a subset of DMG cells expressing wild-type TP53 and mutant ACVR1. RNA-sequencing and phenotypic analyses revealed that LLY-283 could reduce the viability, clonogenicity and invasion of DMG cells in vitro, representing three clinically important phenotypes, but failed to prolong survival in an orthotopic xenograft model. Together, these data show the challenges of DMG treatment and highlight PRMT5 inhibitors for consideration in future studies of combination treatments.https://doi.org/10.1038/s41598-023-48652-x |
| spellingShingle | Elizabeth J. Brown Leire Balaguer-Lluna Adam P. Cribbs Martin Philpott Leticia Campo Molly Browne Jong Fu Wong Udo Oppermann Ángel M. Carcaboso Alex N. Bullock Gillian Farnie PRMT5 inhibition shows in vitro efficacy against H3K27M-altered diffuse midline glioma, but does not extend survival in vivo Scientific Reports |
| title | PRMT5 inhibition shows in vitro efficacy against H3K27M-altered diffuse midline glioma, but does not extend survival in vivo |
| title_full | PRMT5 inhibition shows in vitro efficacy against H3K27M-altered diffuse midline glioma, but does not extend survival in vivo |
| title_fullStr | PRMT5 inhibition shows in vitro efficacy against H3K27M-altered diffuse midline glioma, but does not extend survival in vivo |
| title_full_unstemmed | PRMT5 inhibition shows in vitro efficacy against H3K27M-altered diffuse midline glioma, but does not extend survival in vivo |
| title_short | PRMT5 inhibition shows in vitro efficacy against H3K27M-altered diffuse midline glioma, but does not extend survival in vivo |
| title_sort | prmt5 inhibition shows in vitro efficacy against h3k27m altered diffuse midline glioma but does not extend survival in vivo |
| url | https://doi.org/10.1038/s41598-023-48652-x |
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