ONC212 is a fluorinated imipridone with preclinical efficacy against pancreatic and other malignancies. Although mitochondrial protease ClpP was identified as an ONC212-binding target, the mechanism leading to cancer cell death is incompletely understood. We investigated mitochondrial dysfunction and metabolic rewiring triggered by ONC212 in pancreatic cancer, a deadly malignancy with an urgent need for novel therapeutics. We found ClpP is expressed in pancreatic cancer cells and is required for ONC212 cytotoxicity. ClpX, the regulatory binding partner of ClpP, is suppressed upon ONC212 treatment. Immunoblotting and extracellular flux analysis showed ONC212 impairs oxidative phosphorylation (OXPHOS) with decrease in mitochondrial-derived ATP production. Although collapse of mitochondrial function is observed across ONC212-treated cell lines, only OXPHOS-dependent cells undergo apoptosis. Cells relying on glycolysis undergo growth arrest and upregulate glucose catabolism to prevent ERK1/2 inhibition and apoptosis. Glucose restriction or combination with glycolytic inhibitor 2-deoxy-D-glucose synergize with ONC212 and promote apoptosis in vitro and in vivo . Thus, ONC212 is a novel mitocan targeting oxidative metabolism in pancreatic cancer, leading to different cellular outcomes based on divergent metabolic programs.

中文翻译：

---

ONC212 是一种新型 Mitocan，可协同抑制胰腺癌中的糖酵解

ONC212 是一种氟化亚米哌酮，具有针对胰腺和其他恶性肿瘤的临床前疗效。尽管线粒体蛋白酶 ClpP 被鉴定为 ONC212 结合靶标，但导致癌细胞死亡的机制尚不完全清楚。我们研究了胰腺癌中由 ONC212 引发的线粒体功能障碍和代谢重新布线，这是一种迫切需要新疗法的致命恶性肿瘤。我们发现 ClpP 在胰腺癌细胞中表达并且是 ONC212 细胞毒性所必需的。ClpX 是 ClpP 的调节结合伙伴，在 ONC212 处理后被抑制。免疫印迹和细胞外通量分析表明，ONC212 会损害氧化磷酸化 (OXPHOS)，同时减少线粒体衍生的 ATP 产生。尽管在 ONC212 处理的细胞系中观察到线粒体功能的崩溃，只有 OXPHOS 依赖性细胞发生凋亡。依赖糖酵解的细胞经历生长停滞并上调葡萄糖分解代谢以防止 ERK1/2 抑制和细胞凋亡。葡萄糖限制或与糖酵解抑制剂 2-脱氧-D-葡萄糖的组合与 ONC212 协同作用并在体外和体内促进细胞凋亡。因此，ONC212 是一种新的靶向胰腺癌氧化代谢的线粒体，基于不同的代谢程序导致不同的细胞结果。