Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Shenzhen, P. R. China.
Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, P. R. China.
Autophagy. 2023 Sep;19(9):2618-2619. doi: 10.1080/15548627.2023.2177398. Epub 2023 Feb 15.
Drug-tolerant persister (DTP) cancer cells drive residual tumor and relapse. However, the mechanisms underlying DTP state development are largely unexplored. In a recent study, we determined that PINK1-mediated mitophagy favors DTP generation in the context of MAPK inhibition therapy. DTP cells that persist in the presence of a MAPK inhibitor exhibit mitochondriadependent metabolism. During DTP state development, MYC depletion alleviates the transcriptional repression of , resulting in PINK1 upregulation and mitophagy activation. PINK1-mediated mitophagy is essential for mitochondrial homeostasis in DTP cells. Either knockdown of PINK1 or inhibition of mitophagy eradicates DTP cells and achieves complete responses to MAPK inhibition therapy. This study reveals a novel role of mitophagy as a protective mechanism for DTP development.
耐药性持久（DTP）癌细胞驱动残余肿瘤和复发。然而，DTP 状态发展的机制在很大程度上尚未被探索。在最近的一项研究中，我们确定 PINK1 介导的线粒体自噬有利于 MAPK 抑制治疗背景下 DTP 的产生。在 MAPK 抑制剂存在的情况下持续存在的 DTP 细胞表现出线粒体依赖性代谢。在 DTP 状态发展过程中，MYC 耗竭减轻了 的转录抑制，导致 PINK1 上调和线粒体自噬激活。PINK1 介导的线粒体自噬对于 DTP 细胞中线粒体的动态平衡是必不可少的。敲低 PINK1 或抑制线粒体自噬可根除 DTP 细胞，并实现对 MAPK 抑制治疗的完全反应。这项研究揭示了线粒体自噬作为 DTP 发展的保护机制的新作用。
