Analysis of Compound Synergy in High-Throughput Cellular Screens by Population-Based Lifetime Modeling 英文参考文献.docVIP

Analysis of Compound Synergy in High-Throughput Cellular Screens by Population-Based Lifetime Modeling 英文参考文献.doc

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Analysis of Compound Synergy in High-Throughput Cellular Screens by Population-Based Lifetime Modeling 英文参考文献

AnalysisofCompoundSynergyinHigh-Throughput CellularScreensbyPopulation-BasedLifetimeModeling MartinPeifer1.*,JonathanWeiss1.,MartinL.Sos1.,MirjamKoker1,StefanieHeynck1,ChristianNetzer2, StefanieFischer1,HaridasRode4,DanielRauh4,Jo¨rgRahnenfu¨hrer2,RomanK.Thomas1,3,4* 1MaxPlanckInstituteforNeurologicalResearchwithKlaus-Joachim-Zu¨lchLaboratoriesoftheMaxPlanckSocietyandtheMedicalFacultyoftheUniversityofKo¨ln,Max- Planck Society, Ko¨ln,Germany, 2Department ofStatistics, Technical University ofDortmund, Dortmund,Germany, 3Department IofInternal Medicine andCenter of IntegratedOncologyKo¨ln–Bonn,UniversityofKo¨ln,Ko¨ln,Germany,4ChemicalGenomicsCenteroftheMaxPlanckSociety,Max-PlanckSociety,Dortmund,Germany Abstract Despite the successful introduction of potent anti-cancer therapeutics, most of these drugs lead to only modest tumor- shrinkage or transient responses, followed by re-growth of tumors. Combining different compounds has resulted in enhancedtumorcontrolandprolongedsurvival.However,methodsqueryingtheefficacyofsuchcombinationshavebeen hamperedbylimitedscalability,analyticalresolution,statisticalfeasibility,oracombinationthereof.Wehavedevelopeda theoretical framework modeling cellular viability as a stochastic lifetime process to determine synergistic compound combinationsfromhigh-throughputcellularscreens.Weapplyourmethodtodataderivedfromchemicalperturbationsof 65cancercelllineswithtwoinhibitors.Ouranalysisrevealedsynergyforthecombinationofbothcompoundsinsubsetsof celllines.Bycontrast,incelllinesinwhichinhibitionofoneofbothtargetswassufficienttoinducecelldeath,nosynergy wasdetected,compatiblewiththetopologyoftheoncogenicallyactivatedsignalingnetwork.Insummary,weprovidea toolforthemeasurementofsynergystrengthforcombinationperturbationexperimentsthatmighthelpdefinepathway topologiesanddirectclinicaltrials. Citation:PeiferM,WeissJ,SosML,KokerM,HeynckS,etal.(2010)AnalysisofCompoundSynergyinHigh-ThroughputCellularScreensbyPopulation-Based LifetimeModeling.PLoSONE5(1)

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