2. Academic Validation
  3. Prolyl-tRNA synthetase as a novel therapeutic target in multiple myeloma

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

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. Teru_Hideshima@dfci.harvard.edu.
  • 16 Jerome Lipper Multiple Myeloma Center, LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA. Kenneth_Anderson@dfci.harvard.edu.
  • 17 Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, OX3 7LD, UK. Udo.Oppermann@ndorms.ox.ac.uk.
  • 18 Oxford Centre for Translational Myeloma Research, Botnar Research Centre, University of Oxford, Oxford, OX3 7LD, UK. Udo.Oppermann@ndorms.ox.ac.uk.
  • # Contributed equally.
PMID: 36631435 DOI: 10.1038/s41408-023-00787-w
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.

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