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Nat Commun. 2018 Apr 26;9(1):1677. doi: 10.1038/s41467-018-04033-x.

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

Author information

1
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, 27710, USA.
2
Program in Computational Biology and Bioinformatics, Duke University, Durham, NC, 27710, USA.
3
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, 27710, USA. kris.wood@duke.edu.

Abstract

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.

PMID:
29700304
PMCID:
PMC5919970
DOI:
10.1038/s41467-018-04033-x
[Indexed for MEDLINE]
Free PMC Article

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