Year: 2018
Type: article
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.
Source: Nature Communications
Institution: Duke University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: National Science Foundation, U.S. Department of Defense, Ovarian Cancer Research Fund, Ovarian Cancer Research Fund Alliance, National Institutes of Health, School of Medicine, Duke University, National Cancer Institute, National Institute of General Medical Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G104224009, G1185693225, Medical Scientist Training Program, G2142503422, G306402402, G3335279665, G4119534169, GRADUATE RESEARCH FELLOWSHIP PROGRAM, G4439476886, G5850682332, Selectively targeting apoptosis in PIK3CA mutant colorectal cancers, TARGETING DIFFERENTIAL APOPTOSIS REGULATION IN TRIPLE-NEGATIVE BREAST CANCER, G9000035511
OpenAlex ID: W2803259404