Journal
NATURE
Volume 553, Issue 7687, Pages 222-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature25171
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Funding
- NIH [R01CA101644, U54CA193313, R01CA131126, R01CA178546, R01CA179044, R01CA190891, R01NS061776]
- Chemotherapy Foundation
- Ontario Institute for Cancer Research (OICR) Brain Translational Research Initiative
- American Brain Tumor Association (ABTA)
- Cancer Biology Taining Grant [T32CA009503]
- Italian Association for Cancer Research (AIRC) fellowship
- SickKids Garron Family Cancer Centre Pitblado Discovery
- [NRF-2013R1A6A3A03063888]
- NATIONAL CANCER INSTITUTE [R01CA101644, R01CA131126, R01CA179044, R01CA178546, R01CA190891, U54CA193313, T32CA009503] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS061776] Funding Source: NIH RePORTER
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Chromosomal translocations that generate in-frame oncogenic gene fusions are notable examples of the success of targeted cancer therapies(1-3). We have previously described gene fusions of FGFR3-TACC3 (F3-T3) in 3% of human glioblastoma cases(4). Subsequent studies have reported similar frequencies of F3-T3 in many other cancers, indicating that F3-T3 is a commonly occuring fusion across all tumour types(5,6). F3-T3 fusions are potent oncogenes that confer sensitivity to FGFR inhibitors, but the downstream oncogenic signalling pathways remain unknown(2,4-6). Here we show that human tumours with F3-T3 fusions cluster within transcriptional subgroups that are characterized by the activation of mitochondrial functions. F3-T3 activates oxidative phosphorylation and mitochondrial biogenesis and induces sensitivity to inhibitors of oxidative metabolism. Phosphorylation of the phosphopeptide PIN4 is an intermediate step in the signalling pathway of the activation of mitochondrial metabolism. The F3-T3-PIN4 axis triggers the biogenesis of peroxisomes and the synthesis of new proteins. The anabolic response converges on the PGC1 alpha coactivator through the production of intracellular reactive oxygen species, which enables mitochondrial respiration and tumour growth. These data illustrate the oncogenic circuit engaged by F3-T3 and show that F3-T3-positive tumours rely on mitochondrial respiration, highlighting this pathway as a therapeutic opportunity for the treatment of tumours with F3-T3 fusions. We also provide insights into the genetic alterations that initiate the chain of metabolic responses that drive mitochondrial metabolism in cancer.
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