No abstract

Chromosomal translocations that generate in-frame oncogenic gene fusions are powerful examples of success of targeted cancer therapies1–3. We discovered FGFR3-TACC3 (F3-T3) gene fusions in 3% of human glioblastoma4. 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 types5,6. F3-T3 fusions are potent oncogenes that confer sensitivity to FGFR inhibitors but the downstream oncogenic signaling remains largely unknown2,4–6. 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.

Ion channels represent a large class of drug targets, but their role in brain cancer is underexplored. Here, we identify that chloride intracellular channel 1 (CLIC1) is overexpressed in human central nervous system malignancies, including medulloblastoma, a common pediatric brain cancer. While global knockout does not overtly affect mouse development, genetic deletion of CLIC1 suppresses medulloblastoma growth in xenograft and genetically engineered mouse models. Mechanistically, CLIC1 enriches to the plasma membrane during mitosis and cooperates with potassium channel EAG2 at lipid rafts to regulate cell volume homeostasis. CLIC1 deficiency is associated with elevation of cell/nuclear volume ratio, uncoupling between RNA biosynthesis and cell size increase, and activation of the p38 MAPK pathway that suppresses proliferation. Concurrent knockdown of CLIC1/EAG2 and their evolutionarily conserved channels synergistically suppressed the growth of human medulloblastoma cells and Drosophila melanogaster brain tumors, respectively. These findings establish CLIC1 as a molecular dependency in rapidly dividing medulloblastoma cells, provide insights into the mechanism by which CLIC1 regulates tumorigenesis, and reveal that targeting CLIC1 and its functionally cooperative potassium channel is a disease-intervention strategy.