FDG-PET is a good biomarker of both early response and acquired resistance in BRAFV600 mutant melanomas treated with vemurafenib and the MEK inhibitor GDC-0973.docVIP

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FDG-PET is a good biomarker of both early response and acquired resistance in BRAFV600 mutant melanomas treated with vemurafenib and the MEK inhibitor GDC-0973.doc

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FDG-PET is a good biomarker of both early response and acquired resistance in BRAFV600 mutant melanomas treated with vemurafenib and the MEK inhibitor GDC-0973

Baudyetal.EJNMMIResearch2012,2:22 /content/2/1/22 ORIGINAL RESEARCH OpenAccess FDG-PETisagoodbiomarkerofbothearly responseandacquiredresistancein V600 BRAF mutantmelanomastreated withvemurafenibandtheMEK inhibitorGDC-0973 AndreasRBaudy1,TanerDogan2,JudithEFlores-Mercado1,KlausPHoeflich2,FeiSu3, NicholasvanBruggen1andSimon-PeterWilliams1* Abstract Background:TheBRAFinhibitor,vemurafenib,hasrecentlybeenapprovedforthetreatmentofmetastatic melanomainpatientsharboringBRAFV600 mutations.Currently,dualBRAFandMEKinhibitionareongoingin clinicaltrialswiththegoalofovercomingtheacquiredresistancethathasunfortunatelydevelopedinsome vemurafenibpatients.FDG-PETmeasuresofmetabolicactivityareincreasinglyemployedasapharmacodynamic biomarkerforguidingsingle-agentorcombinationtherapiesbygauginginitialdrugresponseandmonitoring diseaseprogression.However,sincetumorsareinherentlyheterogeneous,investigatingtheeffectsofBRAFand MEKinhibitiononFDGuptakeinapanelofdifferentmelanomascouldhelpinterpretimagingoutcomes. Methods: 18F-FDGuptakewasmeasuredinvitroincellswithwild-typeandmutant(V600)BRAF,andinmelanoma cellswithanacquiredresistancetovemurafenib.Wetreatedthecellswithvemurafenibaloneorincombination withMEKinhibitorGDC-0973.PETimagingwasusedinmicetomeasureFDGuptakeinA375melanomaxenografts andinA375R1,avemurafenib-resistantderivative.Histologicalandbiochemicalstudiesofglucosetransporters,the MAPKandglycolyticpathwayswerealsoundertaken. Results:WedemonstratethatvemurafenibisequallyeffectiveatreducingFDGuptakeincelllinesharboringeither heterozygousorhomozygousBRAFV600butineffectiveincellswithacquiredresistanceorhavingWTBRAFstatus. However,combinationwithGDC-0973resultsinahighlysignificantincreaseofefficacyandinhibitionofFDGuptake acrossalltwentylines.Drug-inducedchangesinFDGuptakewereassociatedwithalteredlevelsofmembraneGLUT-1, andcelllinesharboringRASmutationsdisplayedenhancedFDGuptakeuponexposuretovemurafenib.Interestingly, wefoundthatvemurafenibtreatmentinmicebearingdrug-resistantA375