A metabolic function of FGFR3-TACC3 gene fusions in cancer

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Abstract
Oncogenic FGFR3–TACC3 gene fusions signal through phosphorylated PIN4 to trigger biogenesis of peroxisomes and synthesis of new proteins, enabling mitochondrial respiration and tumour growth. FGFR3-TACC3 gene fusions are oncogenic and have been found in many cancer types, but how they drive tumour growth is unknown. Antonio Iavarone and colleagues show that the fusion protein activates mitochondrial metabolism, which promotes protein synthesis and thereby stimulates tumour growth. The team suggest that this reliance on mitochondrial respiration could open up a new therapeutic route for treating tumours that carry the FGFR3-TACC3 fusion gene. Chromosomal translocations that generate in-frame oncogenic gene fusions are notable examples of the success of targeted cancer therapies1,2,3. We have previously described gene fusions of FGFR3-TACC3 (F3–T3) in 3% of human glioblastoma cases4. 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 types5,6. F3–T3 fusions are potent oncogenes that confer sensitivity to FGFR inhibitors, but the downstream oncogenic signalling pathways remain unknown2,4,5,6. 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 PGC1α 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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