Prolyl-tRNA synthetase as a novel therapeutic target in multiple myeloma PMID: 36631435

ADC Targets in Oncology

2026-04-10

Prolyl-tRNA synthetase as a novel therapeutic target in multiple myeloma

Blood Cancer J. 2023 Jan 12;13(1):12. doi: 10.1038/s41408-023-00787-w.

Keiji Kurata ^# ¹ , Anna James-Bott ^# ² , Mark A Tye ³ ⁴ ⁵ , Leona Yamamoto ¹ , Mehmet K Samur ¹ ⁶ ⁷ , Yu-Tzu Tai ¹ , James Dunford ² , Catrine Johansson ² , Filiz Senbabaoglu ² , Martin Philpott ² , Charlotte Palmer ² , Karthik Ramasamy ⁸ ⁹ , Sarah Gooding ⁸ ¹⁰ , Mihaela Smilova ² , Giorgia Gaeta ² , Manman Guo ² , John C Christianson ² ⁸ , N Connor Payne ³ ¹¹ , Kritika Singh ³ ¹² , Kubra Karagoz ¹³ , Matthew E Stokes ¹³ , Maria Ortiz ¹³ , Patrick Hagner ¹³ , Anjan Thakurta ⁸ ¹³ , Adam Cribbs ² ⁸ , Ralph Mazitschek ³ ⁵ ¹⁴ , Teru Hideshima ¹⁵ , Kenneth C Anderson ¹⁶ , Udo Oppermann ¹⁷ ¹⁸

Affiliations

1. Jerome Lipper Multiple Myeloma Center, LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.
2. Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, OX3 7LD, UK.
3. Center for Systems Biology, Massachusetts General Hospital, Boston, MA, 02114, USA.
4. Harvard Graduate School of Arts and Sciences, Cambridge, MA, 02138, USA.
5. Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
6. Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.
7. Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
8. Oxford Centre for Translational Myeloma Research, Botnar Research Centre, University of Oxford, Oxford, OX3 7LD, UK.
9. Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 7LD, UK.
10. Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 7LD, UK.
11. Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA, 02138, USA.
12. Department of Bioengineering, Northeastern University, Boston, MA, 02115, USA.
13. Bristol Myers Squibb, Summit, NJ, 07901, USA.
14. Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
15. Jerome Lipper Multiple Myeloma Center, LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA. [email protected].
16. Jerome Lipper Multiple Myeloma Center, LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA. [email protected].
17. Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, OX3 7LD, UK. [email protected].
18. Oxford Centre for Translational Myeloma Research, Botnar Research Centre, University of Oxford, Oxford, OX3 7LD, UK. [email protected].
# Contributed equally.

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.