We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Prolyl-tRNA synthetase as a novel therapeutic target in multiple myeloma.
- Authors
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
- Abstract
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.
- Subjects
MULTIPLE myeloma; TRANSCRIPTION factors; PLASMA cells; QUALITY control; IMMUNOGLOBULINS; MONOCLONAL gammopathies; PLASMACYTOMA
- Publication
Blood Cancer Journal, 2023, Vol 13, Issue 1, p1
- ISSN
2044-5385
- Publication type
Article
- DOI
10.1038/s41408-023-00787-w