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Prolyl-tRNA synthetase as a novel therapeutic target in multiple myeloma
Multiple myeloma (MM) is a plasma cell malignancy characterised by aberrant production of immunoglobulins requiring survival mechanisms to adapt to proteotoxic stress. We here show that glutamyl-prolyl-tRNA synthetase (GluProRS) inhibition constitutes a novel therapeutic target. Genomic data suggest...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9834298/ https://www.ncbi.nlm.nih.gov/pubmed/36631435 http://dx.doi.org/10.1038/s41408-023-00787-w |
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author | Kurata, Keiji James-Bott, Anna Tye, Mark A. Yamamoto, Leona Samur, Mehmet K. Tai, Yu-Tzu Dunford, James Johansson, Catrine Senbabaoglu, Filiz Philpott, Martin Palmer, Charlotte Ramasamy, Karthik Gooding, Sarah Smilova, Mihaela Gaeta, Giorgia Guo, Manman Christianson, John C. Payne, N. Connor Singh, Kritika Karagoz, Kubra Stokes, Matthew E. Ortiz, Maria Hagner, Patrick Thakurta, Anjan Cribbs, Adam Mazitschek, Ralph Hideshima, Teru Anderson, Kenneth C. Oppermann, Udo |
author_facet | Kurata, Keiji James-Bott, Anna Tye, Mark A. Yamamoto, Leona Samur, Mehmet K. Tai, Yu-Tzu Dunford, James Johansson, Catrine Senbabaoglu, Filiz Philpott, Martin Palmer, Charlotte Ramasamy, Karthik Gooding, Sarah Smilova, Mihaela Gaeta, Giorgia Guo, Manman Christianson, John C. Payne, N. Connor Singh, Kritika Karagoz, Kubra Stokes, Matthew E. Ortiz, Maria Hagner, Patrick Thakurta, Anjan Cribbs, Adam Mazitschek, Ralph Hideshima, Teru Anderson, Kenneth C. Oppermann, Udo |
author_sort | Kurata, Keiji |
collection | PubMed |
description | Multiple myeloma (MM) is a plasma cell malignancy characterised by aberrant production of immunoglobulins requiring survival mechanisms to adapt to proteotoxic stress. We here show that glutamyl-prolyl-tRNA synthetase (GluProRS) inhibition constitutes a novel therapeutic target. Genomic data suggest that GluProRS promotes disease progression and is associated with poor prognosis, while downregulation in MM cells triggers apoptosis. We developed NCP26, a novel ATP-competitive ProRS inhibitor that demonstrates significant anti-tumour activity in multiple in vitro and in vivo systems and overcomes metabolic adaptation observed with other inhibitor chemotypes. We demonstrate a complex phenotypic response involving protein quality control mechanisms that centers around the ribosome as an integrating hub. Using systems approaches, we identified multiple downregulated proline-rich motif-containing proteins as downstream effectors. These include CD138, transcription factors such as MYC, and transcription factor 3 (TCF3), which we establish as a novel determinant in MM pathobiology through functional and genomic validation. Our preclinical data therefore provide evidence that blockade of prolyl-aminoacylation evokes a complex pro-apoptotic response beyond the canonical integrated stress response and establish a framework for its evaluation in a clinical setting. |
format | Online Article Text |
id | pubmed-9834298 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-98342982023-01-13 Prolyl-tRNA synthetase as a novel therapeutic target in multiple myeloma Kurata, Keiji James-Bott, Anna Tye, Mark A. Yamamoto, Leona Samur, Mehmet K. Tai, Yu-Tzu Dunford, James Johansson, Catrine Senbabaoglu, Filiz Philpott, Martin Palmer, Charlotte Ramasamy, Karthik Gooding, Sarah Smilova, Mihaela Gaeta, Giorgia Guo, Manman Christianson, John C. Payne, N. Connor Singh, Kritika Karagoz, Kubra Stokes, Matthew E. Ortiz, Maria Hagner, Patrick Thakurta, Anjan Cribbs, Adam Mazitschek, Ralph Hideshima, Teru Anderson, Kenneth C. Oppermann, Udo Blood Cancer J Article Multiple myeloma (MM) is a plasma cell malignancy characterised by aberrant production of immunoglobulins requiring survival mechanisms to adapt to proteotoxic stress. We here show that glutamyl-prolyl-tRNA synthetase (GluProRS) inhibition constitutes a novel therapeutic target. Genomic data suggest that GluProRS promotes disease progression and is associated with poor prognosis, while downregulation in MM cells triggers apoptosis. We developed NCP26, a novel ATP-competitive ProRS inhibitor that demonstrates significant anti-tumour activity in multiple in vitro and in vivo systems and overcomes metabolic adaptation observed with other inhibitor chemotypes. We demonstrate a complex phenotypic response involving protein quality control mechanisms that centers around the ribosome as an integrating hub. Using systems approaches, we identified multiple downregulated proline-rich motif-containing proteins as downstream effectors. These include CD138, transcription factors such as MYC, and transcription factor 3 (TCF3), which we establish as a novel determinant in MM pathobiology through functional and genomic validation. Our preclinical data therefore provide evidence that blockade of prolyl-aminoacylation evokes a complex pro-apoptotic response beyond the canonical integrated stress response and establish a framework for its evaluation in a clinical setting. Nature Publishing Group UK 2023-01-12 /pmc/articles/PMC9834298/ /pubmed/36631435 http://dx.doi.org/10.1038/s41408-023-00787-w Text en © The Author(s) 2023, corrected publication 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Kurata, Keiji James-Bott, Anna Tye, Mark A. Yamamoto, Leona Samur, Mehmet K. Tai, Yu-Tzu Dunford, James Johansson, Catrine Senbabaoglu, Filiz Philpott, Martin Palmer, Charlotte Ramasamy, Karthik Gooding, Sarah Smilova, Mihaela Gaeta, Giorgia Guo, Manman Christianson, John C. Payne, N. Connor Singh, Kritika Karagoz, Kubra Stokes, Matthew E. Ortiz, Maria Hagner, Patrick Thakurta, Anjan Cribbs, Adam Mazitschek, Ralph Hideshima, Teru Anderson, Kenneth C. Oppermann, Udo Prolyl-tRNA synthetase as a novel therapeutic target in multiple myeloma |
title | Prolyl-tRNA synthetase as a novel therapeutic target in multiple myeloma |
title_full | Prolyl-tRNA synthetase as a novel therapeutic target in multiple myeloma |
title_fullStr | Prolyl-tRNA synthetase as a novel therapeutic target in multiple myeloma |
title_full_unstemmed | Prolyl-tRNA synthetase as a novel therapeutic target in multiple myeloma |
title_short | Prolyl-tRNA synthetase as a novel therapeutic target in multiple myeloma |
title_sort | prolyl-trna synthetase as a novel therapeutic target in multiple myeloma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9834298/ https://www.ncbi.nlm.nih.gov/pubmed/36631435 http://dx.doi.org/10.1038/s41408-023-00787-w |
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