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.
多发性骨髓瘤是一种浆细胞恶性肿瘤，其特征是免疫球蛋白异常产生，需依赖生存机制适应蛋白毒性应激。本文揭示抑制谷氨酰-脯氨酰-tRNA合成酶可作为新型治疗靶点。基因组数据显示该合成酶能促进疾病进展并与不良预后相关，而在骨髓瘤细胞中下调该酶可引发细胞凋亡。我们研发的新型ATP竞争性ProRS抑制剂NCP26，在多种体外及体内系统中均显示出显著抗肿瘤活性，并能克服其他抑制剂化疗型观察到的代谢适应现象。研究证明该疗法通过以核糖体为整合中心的蛋白质质量控制机制，引发复杂的表型应答。通过系统研究方法，我们识别出多种富含脯氨酸模体的下调蛋白作为下游效应因子，包括CD138、MYC等转录因子及转录因子3。经功能与基因组验证，我们确认转录因子3是多发性骨髓瘤病理生物学的新型决定因子。临床前数据表明，阻断脯氨酰-氨酰化过程能引发超越经典整合应激反应的复杂促凋亡应答，这为临床评估提供了理论框架。
Prolyl-tRNA synthetase as a novel therapeutic target in multiple myeloma
肿瘤(癌症)患者之家