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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2023
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| _version_ | 1826311011511042048 |
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| author | Kurata, K James-Bott, A Tye, MA Yamamoto, L Samur, MK Tai, Y-T Dunford, J Johansson, C Senbabaoglu, F Philpott, M Palmer, C Ramasamy, K Gooding, S Smilova, M Gaeta, G Guo, M Christianson, JC Payne, NC Singh, K Karagoz, K Stokes, ME Ortiz, M Hagner, P Thakurta, A Cribbs, A Mazitschek, R Hideshima, T Anderson, KC Oppermann, U |
| author_facet | Kurata, K James-Bott, A Tye, MA Yamamoto, L Samur, MK Tai, Y-T Dunford, J Johansson, C Senbabaoglu, F Philpott, M Palmer, C Ramasamy, K Gooding, S Smilova, M Gaeta, G Guo, M Christianson, JC Payne, NC Singh, K Karagoz, K Stokes, ME Ortiz, M Hagner, P Thakurta, A Cribbs, A Mazitschek, R Hideshima, T Anderson, KC Oppermann, U |
| author_sort | Kurata, K |
| collection | OXFORD |
| 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. |
| first_indexed | 2024-03-07T08:00:28Z |
| format | Journal article |
| id | oxford-uuid:6dbd0266-cb71-4c3b-8695-1e1387e90c51 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:00:28Z |
| publishDate | 2023 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:6dbd0266-cb71-4c3b-8695-1e1387e90c512023-09-29T16:11:39ZProlyl-tRNA synthetase as a novel therapeutic target in multiple myelomaJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6dbd0266-cb71-4c3b-8695-1e1387e90c51EnglishSymplectic ElementsSpringer Nature2023Kurata, KJames-Bott, ATye, MAYamamoto, LSamur, MKTai, Y-TDunford, JJohansson, CSenbabaoglu, FPhilpott, MPalmer, CRamasamy, KGooding, SSmilova, MGaeta, GGuo, MChristianson, JCPayne, NCSingh, KKaragoz, KStokes, MEOrtiz, MHagner, PThakurta, ACribbs, AMazitschek, RHideshima, TAnderson, KCOppermann, UMultiple 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. |
| spellingShingle | Kurata, K James-Bott, A Tye, MA Yamamoto, L Samur, MK Tai, Y-T Dunford, J Johansson, C Senbabaoglu, F Philpott, M Palmer, C Ramasamy, K Gooding, S Smilova, M Gaeta, G Guo, M Christianson, JC Payne, NC Singh, K Karagoz, K Stokes, ME Ortiz, M Hagner, P Thakurta, A Cribbs, A Mazitschek, R Hideshima, T Anderson, KC Oppermann, U 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 |
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