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

Gray R. Anderson, Suzanne E. Wardell, Merve Cakir, Catherine Yip, Yeong-ran Ahn, Moiez Ali, Alexander P. Yllanes, Christina A. Chao, Donald P. McDonnell and Kris C. Wood ()
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Gray R. Anderson: Duke University
Suzanne E. Wardell: Duke University
Merve Cakir: Duke University
Catherine Yip: Duke University
Yeong-ran Ahn: Duke University
Moiez Ali: Duke University
Alexander P. Yllanes: Duke University
Christina A. Chao: Duke University
Donald P. McDonnell: Duke University
Kris C. Wood: Duke University

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04033-x

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