FeatureReviewAutophagyinCancer:RegulationbySmallMoleculesAllisonS.Limpert,1,3LesterJ.Lambert,1,3NicoleA.Bakas,1NicoleBata,1SonjaN.Brun,2ReubenJ.Shaw,2andNicholasD.P.Cosford1,*Duringtimesofstress,autophagyisacellularprocessthatenablescellstoreclaimdamagedcomponentsbyacontrolledrecyclingpathway.Thismechanismforcellularcatabolismisdysregulatedincancer,withevidenceindicatingthatcancercellsrelyonautophagyinthehypoxicandnutrient-poormicroenvironmentofsolidtumors.Mountingevidencesuggeststhatautophagyhasaroleintheresistanceoftumorstostandard-of-care(SOC)therapies.Therefore,thereissignificantinterestinthediscoveryofsmallmoleculesthatcansafelymodulateautophagy.Inthisreview,wedescriberecentadvancesintheidentificationofnewpharmacologicalcompoundsthatmodulateautophagy,withafocusontheirmodeofaction,valueasprobecompounds,andvalidationaspotentialtherapeutics.TheModulationofAutophagywithSmallMoleculesRestoringenergybalanceduringperiodsofvaryingnutrientavailabilityisafundamentalabilityofeukaryoticcells[1].Thisevolutionarilyconservedcatabolicprocessiscalled‘macro-autophagy’(hereinautophagy;seeGlossary).Duringautophagy,cellsrecyclemacromo-leculesandwholeorganellesbyformingacompartmentcalledanautophagosome,whichsequestersandtrafficsitscontentsforcontrolledfusionwiththelysosome(Figure1).Autophagycanactaseitheraprodeathoraprosurvivalprocessandisbothtissueandmicroenvironmentspecific[2–6].Evidenceforthiscontextualcomplexitycomesfrombothobservationofthephysiologicalconsequencesofgeneticimpairmentofspecificautophagygenesandtheobservedphenotypesintargetedknockoutexperiments[7,8].Furthermore,someautophagyproteinshavenoncanonicalfunctionsincellularpathwaysthatcontrolotherprocesses[9,10].However,autophagyisoftenactivatedinmalignantcancersand,asaconsequence,hasanimportantroleintumorigenesis,tumorevasionandresistance[11].Giventheimportanceofthesepathologicalmechanisms,thereisintenseinterestinthedevelopmentofspecifictherapeuticagentsthatcontrolautophagy[12].Therepurposedautophagyinhibitorschlo...
