Dysregulation of mitochondrial dynamics proteins are a targetable feature of human tumors

• Published in: Nature communications 2018-04, Vol.9 (1), p.1677-13, Article 1677
• Main Authors: Anderson, Gray R., Wardell, Suzanne E., Cakir, Merve, Yip, Catherine, Ahn, Yeong-ran, Ali, Moiez, Yllanes, Alexander P., Chao, Christina A., McDonnell, Donald P., Wood, Kris C.
• Format: Article
• Language: English
• Subjects: 13/106; 13/2; 14/1; 14/19; 45/47; 49/98; 631/67/1059; 631/67/2327; 631/67/68; 631/80/642/333; Animals; Antineoplastic Agents - administration & dosage; Apoptosis; Biomarkers; Cancer; Cell Line, Tumor; Cellular structure; DIABLO protein; Dynamics; Female; Humanities and Social Sciences; Humans; Mice; Mice, Nude; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial DNA; Mitochondrial Dynamics; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; multidisciplinary; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Organelles; Perturbation; Pharmacology; Proteins; Science; Sensitivity; Tumor cell lines; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04033-x

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.