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 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.

Automated summary

Multiple myeloma (MM) is a plasma cell malignancy associated with aberrant immunoglobulin production and proteotoxic stress. In this study, we identified glutamyl-prolyl-tRNA synthetase (GluProRS) as a potential therapeutic target. By developing a novel inhibitor called NCP26, we demonstrated its significant anti-tumour activity in various in vitro and in vivo systems, overcoming metabolic adaptation observed with other inhibitors. Our findings suggest a complex pro-apoptotic response beyond the integrated stress response, involving downregulated proline-rich motif-containing proteins as downstream effectors and establishing a novel determinant in MM pathobiology.