Uponagonistactivation,LXRsundergo
thebindingofLXRstocorepressors,
andtherebythisinverseagonistsup-
pressesLXR-mediatedtranscriptionof
arecentstudylinkedLXR-mediated
roleofLXRiswelldocumented,thecross
talkbetweentheeffectofLXRsignaling
inmetabolismandtheLXR-mediated
Steffensen,K.R.(2012).TrendsPharmacol.Sci.
33,394–404.
T.,andTavazoie,S.F.(2014).Cell156,986–1001.
Tu,Y.,Thupari,J.N.,Kim,E.K.,Pinn,M.L.,Moran,
Stem
Byers
Medical
wh
(5
0
-fluorouracilandcisplatin)inacombi-
nationtreatmentstrategy.Convincingly,
invivoexperimentsusingxenograft
modelsconfirmedtheanti-tumoreffect
ofSR9243andreducedexpressionof
glycolyticlipogenicenzymeswithout
inducingweightloss.
Multiplestudiesreportontheanti-in-
flammatoryfeatureofLXRs(Jakobsson
etal.,2012),andstudieshavereported
thattumorsproduceLXRagoniststo
AlteringtheCourse
TargetingCancer
C.AllisonStewart
1
andLaurenAverett
1
DepartmentofThoracicandHeadandNeck
Correspondence:lbyers@mdanderson.org
http://dx.doi.org/10.1016/j.ccell.2015.06.011
InthisissueofCancerCell,Mohammad
inSCLCwithauniqueepigeneticsig
erationandstemcellmaintenance
icalmodels.
Smallcelllungcarcinoma(SCLC)isoneof
themostgeneticallycomplexcancers
(Peiferetal.,2012).Beyondmutations,
epigeneticchangesalsoplayakeyrole
inpromotingaggressivebehaviorof
4CancerCell28,July13,2015a2015Elsevier
(2015)provideinterestingevidencethat
targetingLXRstosuppressglycolysis
andlipogenesisisapromisingnew
strategyforcancertreatment,further
studiesinvestigatingtheimpactand
associationofLXRsignalinginmeta-
bolism,immunity/inflammation,andpro-
liferationmightunravelnovelmechanisms
toadvancethebattleagainstcancer.
AndtheinverseagonistSR9243could
proveavaluabletoolinthisquest.
ofSmallCellLung
CellsviaLSD1
1,
Oncology,MDAndersonCancerCenter,
etal.describeLSD1,ahistonedemethy
naturetopredictdrugsensitivity.Inhib
ilepromotingcelldifferentiationand
SCLC.31,000patientsarediagnosed
withSCLCannuallyintheUnitedStates,
amajorityofwhomhavewidelydissemi-
nateddiseaseatpresentationandwill
succumbtotheircancerwithinayear
Inc.
Lobaccaro,J.M.,andBaron,S.(2012).Mol.Cell.
Endocrinol.351,129–141.
Villablanca,E.J.,Raccosta,L.,Zhou,D.,Fontana,
R.,Maggioni,D.,Negro,A.,Sanvito,F.,Ponzoni,
M.,Valentinis,B.,Bregni,M.,etal.(2010).Nat.
Med.16,98–105.
Wang,Q.,Ma,X.,Chen,Y.,Zhang,L.,Jiang,M.,Li,
X.,Xiang,R.,Miao,R.,Hajjar,D.P.,Duan,Y.,and
Han,J.(2014).Biochem.J.459,345–354.
Warburg,O.,Wind,F.,andNegelein,E.(1927).
J.Gen.Physiol.8,519–530.
Cancer:
Inhibition
Houston,TX77030,USA
lase,asatherapeutictarget
itionofLSD1reducescellprolif-
reducingtumorgrowthinpreclin-
targetgenestobelowbasallevels.
Furthermore,SR9243sensitizeschemo-
therapytreatmentusingcytotoxicdrugs
modulationoftheimmuneresponse
dealingwithtumorshasonlyrecently
beeninvestigated.WhileFlavenyetal.
T.H.,Ronnett,G.V.,andKuhajda,F.P.(2005).
Endocrinology146,486–493.
Viennois,E.,Mouzat,K.,Dufour,J.,Morel,L.,
aconformationalchangewherethe
corepressorsdissociateandtranscrip-
tionalcoactivatorsarerecruited.SR9243
interactswithLXRsandstrengthens
survivalratesandtumorfreeanimals
inlungcancerxenograftmodelsto
increasedinterferon-gproduction(Wang
etal.,2014).Whiletheanti-inflammatory
Pelicano,H.,Martin,D.S.,Xu,R.H.,andHuang,P.
(2006).Oncogene25,4633–4646.
Pencheva,N.,Buss,C.G.,Posada,J.,Merghoub,
thatSR9243metabolicallyreprograms
therapidlygrowingcancercellsto
‘‘normal’’metaboliccellsthatcannot
sustaincancercellgrowth,andthistrig-
gersapoptosisofthecancercells.The
authorsextendourmolecularunder-
standingofthetranscriptionalnetworkof
LXRsbyintroducinganinverseagonist.
Intheunligandedform,LXRsareassoci-
atedwithtranscriptionalcorepressors.
avoidthebody’stumorimmunesurveil-
lance(Villablancaetal.,2010).Flaveny
etal.(2015)showthatSR9243specifically
inducesexpressionofTNF-aintumor
cellsandsuggestthatSR9243could
‘‘unmask’’tumorstoberecognizedby
theimmunesystem.Cytokinesinthe
tumormicroenvironmentareacknowl-
edgedasimportantfactorsinvolvedin
thecontroloftumorgrowth.Interestingly,
REFERENCES
Bovenga,F.,Sabba`,C.,andMoschetta,A.(2015).
CellMetab.21,517–526.
Flaveny,C.A.,Griffett,K.,El-Gendy,B.E.-D.M.,
Kazantzis,M.,Sengupta,M.,Amelio,A.L.,Chatter-
jee,A.,Walker,J.,Solt,L.A.,Kamenecka,T.M.,
andBurris,T.P.(2015).CancerCell28,thisissue,
42–56.
Jakobsson,T.,Treuter,E.,Gustafsson,J.A.,and
CancerCell
Previews
despitecurrenttreatments.Unlikenon-
smallcelllungcarcinoma(NSCLC),where
agrowingnumberofdruggablegenetic
alterationshavetransformedtreatment
(e.g.,EGFRmutationsandALK,RET,
andROS1fusions),inSCLCthereare
currentlynotargetedtherapieswithes-
tablishedefficacyandtherearenovali-
datedbiomarkerstoguidetreatment
selection.Asaresult,adecades-old
regimenofplatinum-etoposidechemo-
therapyremainsthestandardofcare.
AmajorchallengeintreatingSCLCis
therapidemergenceofdrugresistance,
whichtypicallyoccurswithinmonthsof
completingchemotherapy.Averagesur-
vivalafterrecurrenceisonly4-6months
duetoalackofeffectivesecond-linetreat-
mentoptions.Previousstudiesinavariety
ofcancertypeshavedemonstratedthe
abilityofepigenetictherapytomodulate
theexpressionofgenesregulatingche-
moresistanceandothercriticaloncogenic
behaviors(Azadetal.,2013).
Recently,bycomparingmethylation
patternsinSCLCtumorsversusnormal
lung,Poirieretal.(2015)demonstrated
thatmethylationregulateskeySCLC
genes,includingoverexpressionofBCL2
andsilencingofRB1.Usinghumantu-
mors,patient-derivedxenografts(PDXs),
andcelllines,theythenidentifieddistinct,
reproduciblemethylationsubgroups
withinSCLCthatlikelyrepresentsubsets
withdistincttherapeuticresponses.
Someoftheseepigeneticchangesmay
beregulatedbyrecurringmutationsthat
includeseveralchromatinmodifiersand
epigeneticreaders(Peiferetal.,2012;
Rudinetal.,2012).
Clinically,FDA-approvedindications
forepigenetictherapiesarelimitedto
hematologicalmalignancies.However,
epigeneticmachineryhasemergedas
animportanttargetforadditionaldis-
easesincludinglungcancer.InSCLC,
preclinicalactivityofthehistonedeacety-
laseinhibitorsvorinostatandbelinostat
incombinationwithcisplatin/etoposide
(standardfirst-linetreatment)ortopote-
can(theonlyFDAapprovedsecond-line
therapyforSCLC)hasledtoclinicaltrials
investigatingthesedrugsincombination
withchemotherapy.
InthisissueofCancerCell,Mohammad
etal.(2015)describethediscovery
andcharacterizationofGSK2879552,a
selective,highlypotentsmallmolecule
CancerCell
Previews
inhibitoroflysinedemethylase1(LSD1).
LSD1isahistonemodifierthatmaintains
thepleuripotencyofembryonicstemcells
throughdemethylationofhistoneH3
lysine4(H3K4)andsubsequentrepres-
sionofgenescontrollingcelldifferentia-
tion(Adamoetal.,2011).Priorstudies
haveshownthatLSD1isoverexpressed
inmanycancertypesandthatinhibition
promotesdifferentiationandreduces
cancercellgrowth,migration,andinva-
sion(Lvetal.,2012).
Becauseofitscentralroleinstemcell
maintenanceandcancerprogression,the
authorssoughttoidentifypotentinhibitors
ofLDS1.Thisledultimatelytotheidentifi-
cationofthreeLSD1inhibitorymolecules,
includingGSK2879552andGSK-LSD1.
Furthercharacterizationdemonstrated
thatGSK2879552completelyandirre-
versiblyinactivatesLSD1’senzymatic
activityandishighlyspecificforLSD1,
despiteLSD1havingastructureclosely
relatedtoLSD2,MAO-A,andMAO-B.
Theauthorsthentreated165celllines
representingmultiplecancertypeswith
thenewlydiscoveredinhibitors.Most
wereinsensitivetoGSK2879552;how-
ever,asignificantsubsetofacutemyeloid
leukemia(AML)andSCLCcelllineswere
sensitive.ThesensitivityofAMLtoLSD1
inhibitionwasnotsurprisingbased
onpreviouslypublishedreports(Harris
etal.,2012)andtheestablisheduseof
epigenetictherapiesforAML.Incontrast,
activityinSCLCcelllines(C2430%ofthose
tested)wasanovelandunexpected
observation—andonewiththepotential
toaddressasignificantunmetneed.
Assuch,theauthorsperformeda
detailedinvestigationintotheeffectsof
GSK2879552inSCLCmodels.
Consistentwiththepro-differentiation
effectofLSD1inhibition,GSK2879552
wasprimarilycytostatic,ratherthan
cytotoxic,inSCLCpreclinicalmodels,
resultinginadelayedonsetofgrowth
inhibitioninvitro.Similarly,inSCLCxe-
nografts,tumorsdidnotsignificantly
regress,butrathergrowthwaspro-
nouncedlydelayedintreatedanimals
versuscontrols.
Confidentinthetherapeuticactivityof
GSK2879552inSCLCmodels,theinves-
tigatorsthendemonstratedthatLSD1
proteinishighlyexpressedinpatient
tumorsandthatexpressionofgenes
involvedinneuroendocrinedifferentiation
(ahallmarkofSCLC)changedfollowing
GSK2879552treatment.Next,aninte-
gratedanalysisofepigeneticchanges
causedbyLSD1inhibitionfoundLSD1
andH3K4methylationenrichmentsur-
roundingtranscriptionalstartsitesof
genesinvolvedintheregulationofcell
CancerCell
state.Thesefindingsimplicatearolefor
LSD1inmaintainingSCLCstemness,
withLSD1inhibitionpromotingdifferenti-
ation,similartowhathasbeenobserved
inothercancertypes.
BecauseonlyasubsetofSCLCmodels
demonstratesensitivitytoLSD1inhibi-
tion,theauthorswereinterestedinbio-
markersthatcouldpotentiallyidentify
thoseSCLCpatientslikelytoderivethe
greatestbenefitfromLSD1targeted
therapy.TheyfailedtoidentifymRNA
biomarkersbutdididentifyasetof45
methylationprobeswithdifferencesbe-
tweensensitiveandresistantpreclinical
models.Critically,these45probesalso
separatedSCLChumantumorsand/or
PDXmodelsintotwogroups—supporting
theirpotentialtostratifypatientsbasedon
thelikelihoodofresponse.Mostintrigu-
ingly,theauthorsthendemonstratedthe
abilityoftheirmethylationsignature
‘‘score’’tocorrectlypredicttheresponse
ofthreePDXmodelstotreatmentwith
GSK2879552(Figure1A).
Takentogether,thefindingsinthis
studysupportGSK2879552asanLSD1
inhibitorwithpotentialactivityagainst
SCLC.Today,patientswithSCLC
continuetobetreatedwitha‘‘one-size-
fits-all’’approachusingchemotherapy
regimensthathavenotsignificantly
changedin30years.However,agrowing
understandingofthemolecularheteroge-
neityofthisdiseaseshouldallowusto
exploituniquemolecularfeaturesofan
individual’scancertotargetspecific
therapeuticvulnerabilities.Thepreclinical
findingsdescribedinthisissueareof
particulartranslationalrelevancegiven
acurrentmulticenterphase1studyof
GSK2879552inpatientswithrelapsed/
refractorySCLC(NCT02034123).
Giventhecriticalissueofdrugresis-
tanceinSCLCandthepotentialcontribu-
tionofstem-cellenrichmenttothisclinical
problem,theintroductionofanovel
drugthatpromotesdifferentiationmay
beespeciallyeffectiveintreatingorpre-
ventingSCLCrelapse.SCLCcelllines
containlargepopulationsofstemcells
(Sullivanetal.,2010),whichareimpli-
catedinchemotherapyresistanceand
metastasis,bothofwhicharemajorchal-
lengesinSCLC.Infact,CD133levels,a
markerofstemcells,wereelevatedin
SCLCtumorsfollowingchemotherapy
(Sarvietal.,2014).Bypromotingdifferen-
tiation,ratherthanstemcellmaintenance,
28,July13,2015a2015ElsevierInc.5
recurrence(Figure1B).Inconclusion,
thisisapromisingnoveltherapeuticagent
CancerCell
Previews
LSD1inhibitionmayprolongsensitivityto
chemotherapy.
Theworkpresentedhererepresents
anexcitingsteptowardthepossibility
ofpersonalizedcancertherapyin
SCLC.Nevertheless,importantquestions
remain.First,furtherinvestigationintothe
mechanismofactionofGSK2879552in
SCLCiswarrantedgiventhatmethylation
markers—butnotmRNAlevels(which
shouldchangeinresponsetoalterations
inmethylation)—werepredictiveofdrug
response.Thisraisesthepossibilityof
additionalmechanismsbywhichthe
Figure1.ProposedDNAHypomethylationSignat
(A)Asignatureof45differentiallymethylatedCpGswas
hibitorGSK2879552.Totesttheperformanceofthe
(PDXs)werescoredtopredictdrugresponse.TwoPDXs
spondedtoGSK2879552,whereasaPDXwithanegati
(B)ClinicalschemaofproposedmechanismofGSK2879552
ulation.Followinganinitialtreatmentperiodwithchemotherapy
SCLCtumorleadstofurtherregressionanddiseasecontrol.
6CancerCell28,July13,2015a2015Elsevier
LSD1inhibitormaybeacting,suchas
decreasingthestabilityofE2F1protein
(KontakiandTalianidis,2010).SCLCis
anE2F1‘‘addicted’’tumorduetothe
lossofRB1,andthismaycontributeto
itssensitivitytoLSD1inhibition.Second,
theongoingclinicaltrialwillbeginto
addresswhetherGSK2879552hassingle
agentactivityinpatientswithrelapse.
However,thisdrugmaybemosteffective
inthemaintenancesettingafterthebulky
diseasehasbeenreducedbychemo-
therapyandacancerstemcellpopulation
maybeenrichedandpoisedfordisease
Nat.Genet.44,1104–1110.
Sarvi,S.,Mackinnon,A.C.,Avlonitis,N.,Bradley,
uretoPredictSCLCSensitivity
associatedwithinvitrosensitivitytotheLSD1in-
methylationsignature,patient-derivedxenografts
withpositivemethylationsignaturescoresre-
vescorewasresistant.
inabiomarkerselectedSCLCpatientpop-
,treatmentofstem-cellenrichedresidual
Inc.
M.,Rintoul,R.C.,Rassl,D.M.,Wang,W.,Forbes,
S.J.,Gregory,C.D.,andSethi,T.(2014).Cancer
Res.74,1554–1565.
Sullivan,J.P.,Spinola,M.,Dodge,M.,Raso,M.G.,
Behrens,C.,Gao,B.,Schuster,K.,Shao,C.,
Larsen,J.E.,Sullivan,L.A.,etal.(2010).Cancer
Res.70,9937–9948.
Poirier,J.T.,Gardner,E.E.,Connis,N.,Moreira,
A.L.,deStanchina,E.,Hann,C.L.,andRudin,
C.M.(2015).Oncogene.PublishedonlineMarch
9,2015.http://dx.doi.org/10.1038/onc.2015.38.
Rudin,C.M.,Durinck,S.,Stawiski,E.W.,Poirier,
J.T.,Modrusan,Z.,Shames,D.S.,Bergbower,
E.A.,Guan,Y.,Shin,J.,Guillory,J.,etal.(2012).
Nat.Genet.44,1111–1116.
withunexpectedactivityinSCLC.In
additiontointroducingpotentiallyactive
epigenetictherapy,thisstudyprovides
thefirstepigeneticbiomarkerforSCLC
andrepresentsasteptowardmore
tailoredtreatmentforSCLCpatients.
ACKNOWLEDGMENTS
L.A.B.issupportedinpartbytheNCICancerClin-
icalInvestigatorTeamLeadershipAward(P30
CA016672),UTLungSpore(5P50CA070907),
TheSidneyKimmelFoundationforCancer
Research,R.LeeClarkFellowAward(supported
bytheJeaneF.ShelbyScholarshipFund),and
theMDACCPhysicianScientistAward.
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