1450|CANCERDISCOVERYDecember2017www.aacrjournals.orgmTORandHDACInhibitorsConvergeontheTXNIP/ThioredoxinPathwaytoCauseCatastrophicOxidativeStressandRegressionofRAS-DrivenTumorsClareF.Malone1,2,ChloeEmerson1,2,RachelIngraham1,2,WilliamBarbosa1,2,StephanieGuerra1,2,HaejinYoon3,LinL.Liu4,FranziskaMichor4,MarciaHaigis3,KayF.Macleod5,OphéliaMaertens1,2,6,andKarenCichowski1,2,6RESEARCHARTICLEABSTRACTAlthoughagentsthatinhibitspecificoncogenickinaseshavebeensuccessfulinasubsetofcancers,therearecurrentlyfewtreatmentoptionsformalignanciesthatlackatargetableoncogenicdriver.Nevertheless,duringtumorevolutioncancersengageavarietyofprotectivepathways,whichmayprovidealternativeactionabledependencies.Here,weidentifyapromisingcombinationtherapythatkillsNF1-mutanttumorsbytriggeringcatastrophicoxidativestress.Specifically,weshowthatmTORandHDACinhibitorskillaggressivenervoussystemmalignan-ciesandshrinktumorsinvivobyconvergingontheTXNIP/thioredoxinantioxidantpathway,throughcooperativeeffectsonchromatinandtranscription.Accordingly,TXNIPtriggerscelldeathbyinhibitingthioredoxinandactivatingapoptosissignal-regulatingkinase1(ASK1).Moreover,thisdrugcombina-tionalsokillsNF1-mutantandKRAS-mutantnon–smallcelllungcancers.Together,thesestudiesidentifyapromisingtherapeuticcombinationforseveralcurrentlyuntreatablemalignanciesandrevealaprotectivenodalpointofconvergencebetweentheseimportantepigeneticandoncogenicenzymes.SIGNIFICANCE:TherearenoeffectivetherapiesforNF1-orRAS-mutantcancers.Weshowthatcom-binedmTOR/HDACinhibitorskilltheseRAS-driventumorsbycausingcatastrophicoxidativestress.Thisstudyidentifiesapromisingtherapeuticcombinationanddemonstratesthatselectiveenhance-mentofoxidativestressmaybemorebroadlyexploitedfordevelopingcancertherapies.CancerDiscov;7(12);1450–63.©2017AACR.1GeneticsDivision,DepartmentofMedicine,BrighamandWomen’sHospital,Boston,Massachusetts.2HarvardMedicalSchool,Boston,Massachusetts.3DepartmentofCellBiology,LudwigCenteratHarvard,HarvardMedicalSchool,Boston,Massachusetts.4D...
