Dysregulation of mitochondrial dynamics proteins are a targetable feature of human tumors.
Dysregulation of mitochondrial dynamics proteins are a targetable feature of human tumors.
复制标题
DOI：
10.1038/s41467-018-04033-x
复制
发表时间：
2018-04-26
影响因子：
16.6
通讯作者：
Wood KC
中科院分区：
文献类型：
--
作者：
Anderson GR;Wardell SE;Cakir M;Yip C;Ahn YR;Ali M;Yllanes AP;Chao CA;McDonnell DP;Wood KC
改变的线粒体动力学可以广泛地影响肿瘤细胞生理学。使用癌细胞系和人类肿瘤的遗传和药理学分析，我们在这里确定线粒体动力学网络的扰动也会导致特定的治疗脆弱性。特别地，通过不同的机制，具有增加的线粒体片段化或连接性的肿瘤对SMAC模拟物过敏，SMAC模拟物是一类通过抑制IAP诱导细胞凋亡的化合物，并且其稳健的敏感性生物标志物仍有待鉴定。此外，由于驱动癌基因对线粒体动力学施加显性控制，因此癌基因靶向疗法可用于通过其对裂变/融合动力学的影响使肿瘤对SMAC模拟物敏感。总的来说，这些数据表明，线粒体动力学网络的扰动在不同的人类肿瘤中诱导了可靶向的脆弱性，更广泛地说，表明细胞器的结构、活性和运输的改变可能促进额外的癌症治疗机会。线粒体动力学调节关键过程。在这里，作者表明，调节线粒体动力学的基因在人类癌症中经常扩增，并且这些改变与药物敏感性的变化有关，包括对靶向Smac模拟物的敏感性增加。
Altered mitochondrial dynamics can broadly impact tumor cell physiology. Using genetic and pharmacological profiling of cancer cell lines and human tumors, we here establish that perturbations to the mitochondrial dynamics network also result in specific therapeutic vulnerabilities. In particular, through distinct mechanisms, tumors with increased mitochondrial fragmentation or connectivity are hypersensitive to SMAC mimetics, a class of compounds that induce apoptosis through inhibition of IAPs and for which robust sensitivity biomarkers remain to be identified. Further, because driver oncogenes exert dominant control over mitochondrial dynamics, oncogene-targeted therapies can be used to sensitize tumors to SMAC mimetics via their effects on fission/fusion dynamics. Collectively, these data demonstrate that perturbations to the mitochondrial dynamics network induce targetable vulnerabilities across diverse human tumors and, more broadly, suggest that the altered structures, activities, and trafficking of cellular organelles may facilitate additional cancer therapeutic opportunities. Mitochondrial dynamics regulate critical processes. Here the authors show that genes regulating mitochondrial dynamics are frequently amplified in human cancers, and that these alterations are associated with changes in drug sensitivity including increased sensitivity to the apoptosis-targeting Smac mimetics.
登录
查看更多内容
影响因子：
3.5
作者：
Chen H;Chan DC
通讯作者：
Chan DC
影响因子：
3.5
作者：
Ban T;Heymann JA;Song Z;Hinshaw JE;Chan DC
通讯作者：
Chan DC
影响因子：
29
作者：
Chen H;Chan DC
通讯作者：
Chan DC
影响因子：
7.3
作者：
Abuarab, Nada;Munsey, Tim S.;Sivaprasadarao, Asipu
通讯作者：
Sivaprasadarao, Asipu
影响因子：
16
作者：
Kashatus, Jennifer A.;Nascimento, Aldo;Myers, Lindsey J.;Sher, Annie;Byrne, Frances L.;Hoehn, Kyle L.;Counter, Christopher M.;Kashatus, David F.
通讯作者：
Kashatus, David F.