A metabolic function of FGFR3-TACC3 gene fusions in cancer

Abstract

Chromosomal translocations that generate in-frame oncogenic gene fusions are powerful examples of success of targeted cancer therapies ^{1– 3} . We discovered FGFR3-TACC3 (F3-T3) gene fusions in 3% of human glioblastoma ⁴ . Subsequent studies reported similar frequencies of F3-T3 in many other cancers, thus qualifying F3-T3 as one of the most recurrent fusions across all tumor types ^{5, 6} . F3-T3 fusions are potent oncogenes that confer sensitivity to FGFR inhibitors but the downstream oncogenic signaling remains largely unknown ^{2, 4– 6} . Here, we report that tumors harboring F3-T3 cluster within transcriptional subgroups characterized by activation of mitochondrial functions. F3-T3 activates oxidative phosphorylation and mitochondrial biogenesis and induces sensitivity to inhibitors of oxidative metabolism. We show that phosphorylation of PIN4 is the signaling intermediate for the activation of mitochondrial metabolism. The F3-T3-PIN4 axis triggers peroxisome biogenesis and new protein synthesis. The anabolic response converges on PGC1α through intracellular ROS, enabling mitochondrial respiration and tumor growth. Our analyses uncover the oncogenic circuit engaged by F3-T3, expose reliance on mitochondrial respiration as unexpected therapeutic opportunity for F3-T3-positive tumors and provide a clue to the genetic alterations that initiate the chain of metabolic responses driving mitochondrial metabolism in cancer.