Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), F-13009 Marseille, France.
Aix Marseille Université, CNRS, Centrale Marseille, ISM2, F-13013 Marseille, France.
Cell Rep Med. 2020 Nov 17;1(8):100143. doi: 10.1016/j.xcrm.2020.100143.
Mitochondrial respiration (oxidative phosphorylation, OXPHOS) is an emerging target in currently refractory cancers such as pancreatic ductal adenocarcinoma (PDAC). However, the variability of energetic metabolic adaptations between PDAC patients has not been assessed in functional investigations. In this work, we demonstrate that OXPHOS rates are highly heterogeneous between patient tumors, and that high OXPHOS tumors are enriched in mitochondrial respiratory complex I at protein and mRNA levels. Therefore, we treated PDAC cells with phenformin (complex I inhibitor) in combination with standard chemotherapy (gemcitabine), showing that this treatment is synergistic specifically in high OXPHOS cells. Furthermore, phenformin cooperates with gemcitabine in high OXPHOS tumors in two orthotopic mouse models (xenografts and syngeneic allografts). In conclusion, this work proposes a strategy to identify PDAC patients likely to respond to the targeting of mitochondrial energetic metabolism in combination with chemotherapy, and that phenformin should be clinically tested in appropriate PDAC patient subpopulations.
线粒体呼吸（氧化磷酸化，OXPHOS）是目前难治性癌症（如胰腺导管腺癌 (PDAC)）的一个新兴靶点。然而，在功能研究中，尚未评估 PDAC 患者之间能量代谢适应性的可变性。在这项工作中，我们证明了 OXPHOS 率在患者肿瘤之间存在高度异质性，并且高 OXPHOS 肿瘤在蛋白质和 mRNA 水平上富含线粒体呼吸复合物 I。因此，我们用苯乙双胍（复合物 I 抑制剂）联合标准化疗（吉西他滨）治疗 PDAC 细胞，表明这种治疗在高 OXPHOS 细胞中具有协同作用。此外，苯乙双胍在两种原位小鼠模型（异种移植和同基因同种异体移植）中的高 OXPHOS 肿瘤中与吉西他滨协同作用。总之，这项工作提出了一种策略，可以识别可能对化疗联合靶向线粒体能量代谢有反应的 PDAC 患者，并且应该在适当的 PDAC 患者亚群中临床测试苯乙双胍。
