PI3K_AKT通路研究

BiochemicalPharmacology90(2014)197–207

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BiochemicalPharmacology

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Commentary

TargetingPI3K/AKT/mTORpathwayinnonsmallcelllungcancer

ClaudiaFumarola,MaraA.Bonelli,PierGiorgioPetronini,RobertaR.Al eri*

UnitofExperimentalOncology,ClinicalandExperimentalMedicineDepartment,UniversityofParma,ViaVolturno39,43126Parma,Italy

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ABSTRACT

Articlehistory:

Received31March2014Accepted16May2014

Availableonline24May2014

Keywords:PI3KAKTmTORNSCLCSQCLC

WhilePI3K/AKT/mTORpathwayisalteredinavarietyofcancersincludingnonsmallcelllungcancer,abnormalitiesinthispathwayaremorecommoninsquamouscelllungcarcinomathaninadenocarcinomaofthelung.Moreover,aberrantactivationofPI3K/AKT/mTORpathwayisoneofthemechanismsofacquiredresistancetoEGFR-TKinhibitorsinpatientswithadenocarcinomacarryingEGFRactivatingmutations.

SeveralinhibitorsofthePI3Kpathwayareundergoingevaluationinpreclinicalandclinicalstudies.TheseincludepanandselectiveinhibitorsofPI3K,AKTinhibitors,rapamycinandrapalogsformTORinhibition,dualmTORC1-mTORC2inhibitorsanddualPI3K-mTORinhibitors.

Thisreviewfocusesonrecentpreclinicalandclinicaldataontheef cacyofPI3KpathwayinhibitorsinNSCLCeitherasmonotherapyapproachorincombinationwithchemotherapyorwithdrugsthattargetothersignalingtransductionpathways.

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1.PI3K/AKT/mTORpathway

ThetreatmentofNSCLChasbeenchangedthankstoemergingnewtherapiesdirectedagainstde nedmoleculartargets.InitialexperiencewithtargetedtherapiesinunselectedpatientscarryingNSCLCresultedinmodesteffects.Incontrast,thesetherapieshaveledtoremarkableeffectivenesswhenadministeredtomolecularlyselectedpopulations.

EGFRandKRASgenemutations,METampli cation,EML4-ALKrearrangementsarewidelyrecognizedalterationsinvolvedinthepathobiologyoflungcancerwithclinicalimpactforNSCLCtreatment.Recently,newoncogenicgenealterationshavebeenidenti edinNSCLC,includingHER2exon20insertionmutations,BRAFmutations,FGFR1ampli cation,DDR2mutations,RETandROS1rearrangements,andalterationsofPIK3/AKT/mTORpath-way.

ThePI3K/AKT/mTORpathwayisasignaltransductionpathwayinvolvedintheregulationofmultiplecellularfunctionsincluding

Abbreviations:AE,adverseevent;CR,completeresponse;EGFR,epidermalgrowthfactorreceptor;MTD,maximumtolerateddose;NSCLC,nonsmallcelllungcancer;ORR,overallresponserate;OS,overallsurvival;mTOR,mammaliantargetofrapamycin;PFS,progressionfreesurvival;PI3K,phosphatidylinositol3-kinase;PR,partialresponse;RTK,receptortyrosinekinase;SQCLC,squamouscellcarcinoma;SD,stabledisease;TKI,tyrosinekinaseinhibitor.

*Correspondingauthor.Tel.:+39521903768;fax:+39521903742.E-mailaddresses:claudia.fumarola@unipr.it(C.Fumarola),

mara.bonelli@unipr.it(M.A.Bonelli),piergiorgio.petronini@unipr.it(P.G.Petronini),roberta.al eri@unipr.it(R.R.Al eri).

cellproliferation,survival,differentiation,adhesion,motilityandinvasion.

Thepathwayisswitchedonthroughactivationofmembranereceptors,includingtyrosine-kinasereceptors(RTKs),suchasEGFR,HER2,IGFR-1,VEGFRandPDGFR.ActivatedreceptortyrosinekinasesrecruittothecellmembraneacomplexincludingPI3Ks(Fig.1).PI3Ksphosphorylatethephosphatidylinositol(PtdIns)lipidsubstratesintheplasmamembrane,generatingPtdIns(3,4,5)P3,PtdIns(3,4)P2andPtdIns3P,whichinteractwithmultipleeffectorproteinsandtransducethesignalingfromthemembranetothecytoplasm.PI3Ksaredividedintothreesubclassesonthebasisofstructure,regulation,andlipidsubstratespeci city.ClassIPI3Ksareheterodimericproteinsformedofap110catalyticsubunitandap85regulatorysubunitprimarilyinvolvedinthepathogenesisofhumancancer[1].

ClassIAconsistofthecatalyticsubunitsp110a,p110b,andp110dencodedbyPIK3CA,PIK3CB,andPIK3CDgenes,respectively,thatassociatewithoneofthe veisoformsoftheregulatorysubunitsp85(p85a,p85b,p55a,p55g,p50a),whereasclassIBentailsp110gencodedbyPIK3CGthatbindsoneoftworelatedregulatorysubunits,p101andp87.Oftheseproteins,p110aandp110bareubiquitouslyexpressed,whereasp110dandp110garemainlyfoundinimmuneandhematopoieticcells[2].ClassIPI3KsusePtdIns(4,5)P2assubstrateandcanbeactivatedbyRTKsandGprotein-coupledreceptors,viaphosphotyrosinebindingoftheSrc-homology2(SH2)domainpresentinthep85regulatorysubunitwiththecytoplasmicdomainsofRTKs.Engagementofthep85SH2domainsbypTyrrelievesthep85-mediatedinhibitionofp110

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