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Nature:FunctionofFGFR3-TACC3GeneFusionsinCancer

Inanewstudy,researchersfromtheColumbiaUniversityMedicalCenter(CUMC)foundthatthe fusionof two adjacentgenes can leadtooverexpression of mitochondria andanincrease in the amountoffuelneededforthecrazygrowthofcells,leadingtocancer.Theyalsofoundthatdrugs that target this newly identified cancer pathway can stop tumor growth in human cancer cells andinamousemodelofbraincancer.

Glioblastomaisthemostcommonandinvasiveprimarybraincancer.Ina2012studypublishedin

Science(Science,doi:10.1126/science.1220834),theCUMCteamfoundthatsomeglioblastoma

caseswerecausedbythefusionoftwogenes,FGFR3andTACC3.Atthetime,itwasthoughtthat

thisgeneticfusionwaslimitedtoasubsetofbraintumors,affectingabout300patientseachyear

intheUnitedStates.

However, since then, other researchers have observed that this same genetic fusion exists in a subset of lung, esophageal, breast, head and neck, cervical and bladder cancers, affecting thousands of cancer patients. "This is probably the single most common gene fusion in human cancers," said Antonio Iavarone, MD, a professor of pathology and cell biology professor of neurologyattheCUMCInstituteforCancerGeneticsandco-authorofthepaper,“andwewanted to determine how the FGFR3-TACC3 fusion Induce and maintain cancer so that we may identify newtargetsfordrugtherapy."

Mitochondrial changes have long been observed in cancers, but mitochondrial activity and cellular metabolism have been found only recently to correlate with certain cancers. However, the mechanism by which mutations in genes alter mitochondrial activity and promote tumor growthisunknown.

In the current study, these researchers compared the activity of thousands of genes in FGFR3-TACC3-carrying and non-FGFR3-TACC3-bearing cancer cells. They found that this fusion greatly increased the number of mitochondria and increased their activity.Since cancerous cells require large amounts of energy to rapidly divide and grow, these cancerous cells thrive when mitochondrialactivityincreases.

Through a variety of experimental techniques, these researchers determined that this gene fusion initiates a series of events that enhance mitochondrial activity. First, FGFR3-TACC3

activatesaproteincalledPIN4.Uponactivation,PIN4migratesintoperoxisomes.Asanorganelle,

peroxisomes degrade fat into substances that increase mitochondrial activity. Triggered by activated PIN4, the number of peroxisomes increased 4 to 5 times, releasing a large amount of oxidant. Finally,these oxidants induce PGC1α production. As a key regulator of mitochondrial metabolism,PGC1α increasesmitochondrialactivityandenergyproduction.

Anna Lasorella,PhD,co-author of the paper,andprofessor of cell biology at the CUMC Institute for Cancer Genetics, said: "Our research provides the first clue to how oncogenes activate mitochondrialmetabolism,whichisacruciallong-standingareaincancerresearchandprovided

the first direct evidence of the involvement of peroxisomes in cancer production, giving us new insightsonhowwecandisruptthefuelsupplytocancer."

In another experiment, treatment of human brain cancer cells containing FGFR3-TACC3 with a mitochondrialinhibitorblockedenergyproductionincancercellsandsignificantlyslowedtumor growth.Thiseffectisalsoobservedinhumanbraincancermousemodels thatcontainthisgene fusion. Dr. Lavarone speculates that a dual treatment may be needed for patients with FGFR3-TACC3 tumors. In previous studies, these researchers have found that drugs that inhibit

FGFR3kinaseincreasesurvivalwhentestedinaglioblastomamousemodel.FGFR3kinaseassists

inthefunctionoftheproteinproducedbythisfusiongene.

Now,Dr.MarcSansonofthePitiéSalpêtrièreHospitalinParis,France,co-authorofthepaper,is testing these drugs in patients with recurrent glioblastoma in a clinical trial. "Drugs that inhibit activekinaseshavebeentestedinsomecancersandhavehadencouragingresults,butinevitably, they are resistant to these drugs and the tumors have relapsed," said Dr. Lavarone. However, direct targeting of mitochondrial metabolism and FGFR3-TACC3 may prevent this drug-resistant productionandtumorrecurrence."

Based on the findings of the study, these researchers are now contemplating the possibility of addingmitochondrialinhibitorstothetherapiesinpatientsenrolledinthetrial.

The researchers are currently testing this dual treatment in human cancer cells and animal models.