Prolyl-tRNA synthetase as a novel therapeutic target in multiple myeloma.
Kurata K., Bott A-J., 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.
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.