Current Topics in Microbiology and Immunology Volume 347 Series Editors Klaus Aktories Albert-Ludwigs-Universita¨tFreiburg,Medizinische Fakulta¨t, Institutfu¨rExperimentelle undKlinischePharmakologie undToxikologie,Abt. I,Albertstr.25, 79104Freiburg, Germany Richard W.Compans EmoryUniversity Schoolof Medicine, Department ofMicrobiologyand Immunology, 3001Rollins Research Center,Atlanta, GA30322, USA Max D.Cooper Department of PathologyandLaboratory Medicine, GeorgiaResearch Alliance, EmoryUniversity, 1462Clifton Road,Atlanta, GA30322, USA Yuri Y.Gleba ICONGenetics AG,Biozentrum Halle,Weinbergweg 22, Halle 6120,Germany Tasuku Honjo Department of Medical Chemistry, KyotoUniversity, Facultyof Medicine, Yoshida, Sakyo-ku,Kyoto606-8501, Japan Hilary Koprowski ThomasJefferson University, Department ofCancer Biology, BiotechnologyFoundation Laboratories, 1020Locust Street,Suite M85JAH, Philadelphia, PA 19107-6799,USA BernardMalissen Centre d’Immunologiede Marseille-Luminy, ParcScientifique deLuminy, Case906, Marseille Cedex 9 13288, France FritzMelchers Max PlanckInstituteforInfection Biology, Charite´platz1, 10117Berlin,Germany Michael B.A. Oldstone ViralImmunobiologyLaboratory,Dept.ofImmunology&MicrobialScience,TheScripps Research Institute, 10550North TorreyPines, LaJolla, CA 92037, USA SjurOlsnes Department of Biochemistry, InstituteforCancer Research,The Norwegian Radium Hospital,Montebello 0310Oslo, Norway Peter K.Vogt TheScrippsResearchInstitute,Dept.ofMolecular&ExperimentalMedicine,10550North TorreyPines Road.BCC-239, LaJolla, CA 92037, USA Current Topics in Microbiology and Immunology Previously published volumes Further volumes can be found at springer.com Vol.321:Beutler,Bruce(Ed.): Vol.334:McGavern,Dorian;Dustin,Micheal(Eds.): Immunology,PhenotypeFirst:HowMutations VisualizingImmunity.2009. HaveEstablishedNewPrinciplesand ISBN978-3-540-93862-0 PathwaysinImmunology.2008. Vol.335:Levine,Beth;Yoshimori,Tamotsu; ISBN978-3-540-75202-8 Deretic,Vojo(Eds.): Vol.322:Romeo,Tony(Ed.): AutophagyinInfectionandImmunity.2009. BacterialBiofilms.2008. ISBN978-3-642-00301-1 ISBN978-3-540-75417-6 Vol.336:Kielian,Tammy(Ed.): Vol.323:Tracy,Steven;Oberste,M.Steven; Toll-likeReceptors:RolesinInfectionand Drescher,KristenM.(Eds.): Neuropathology.2009. GroupBCoxsackieviruses.2008. ISBN978-3-642-00548-0 ISBN978-3-540-75545-6 Vol.337:Sasakawa,Chihiro(Ed.): Vol.324:Nomura,Tatsuji;Watanabe, MolecularMechanismsofBacterialInfection Takeshi;Habu,Sonoko(Eds.): viatheGut.2009. HumanizedMice.2008. ISBN978-3-642-01845-9 ISBN978-3-540-75646-0 Vol.338:Rothman,AlanL.(Ed.): DengueVirus.2009. Vol.325:Shenk,ThomasE.;Stinski,MarkF.(Eds.): ISBN978-3-642-02214-2 HumanCytomegalovirus.2008. 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ISBN978-3-642-13331-2 ISBN978-3-540-70616-8 Vol.345:Simon,M.Celeste(Ed.): Vol.331:Villiers,E.M.de(Ed.): DiverseEffectsofHypoxiaonTumor TTViruses.2009.ISBN978-3-540-70917-8 Progression.2010. ISBN978-3-642-13328-2 Vol.332:KarasevA.(Ed.): PlantproducedMicrobialVaccines.2009. Vol.346:ChristianRommel;BartVanhaesebroeck; ISBN978-3-540-70857-5 PeterK.Vogt(Ed.): Phosphoinositide3-kinaseinHealth Vol.333:Compans,RichardW.; andDisease.2010. Orenstein,WalterA.(Eds.): ISBN978-3-642-13662-7 VaccinesforPandemicInfluenza.2009. ISBN978-3-540-92164-6 Christian Rommel Bart Vanhaesebroeck l l Peter K. Vogt Editors Phosphoinositide 3-kinase in Health and Disease Volume 2 Editors Dr.ChristianRommel Prof.Dr.BartVanhaesebroeck Intellikine QueenMary,UniversityofLondon 10931NorthTorreyPinesRoad CentreforCellSignalling LaJolla,CA92037 InstituteofCancer USA CharterhouseSquare [email protected] LondonEC1M6BQ UnitedKingdom Prof.Dr.PeterK.Vogt [email protected] TheScrippsResearchInstitute Dept.Molecular&ExperimentalMedicine 10550NorthTorreyPinesRoad LaJolla,CA92037 USA [email protected] ISSN0070-217X ISBN:978-3-642-14815-6 e-ISBN:978-3-642-14816-3 DOI10.1007/978-3-642-14816-3 SpringerHeidelbergDordrechtLondonNewYork LibraryofCongressControlNumber:2010936822 #Springer-VerlagBerlinHeidelberg2010 Thisworkissubjecttocopyright.Allrightsarereserved,whetherthewholeorpartofthematerialis concerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation,broadcasting, reproductiononmicrofilmorinanyotherway,andstorageindatabanks.Duplicationofthispublication orpartsthereofispermittedonlyundertheprovisionsoftheGermanCopyrightLawofSeptember9, 1965,initscurrentversion,andpermissionforusemustalwaysbeobtainedfromSpringer.Violations areliabletoprosecutionundertheGermanCopyrightLaw. Theuseofgeneraldescriptivenames,registerednames,trademarks,etc.inthispublicationdoesnot imply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevantprotec- tivelawsandregulationsandthereforefreeforgeneraluse. Coverdesign:WMXDesignGmbH,Heidelberg,Germany Printedonacid-freepaper SpringerispartofSpringerScience+BusinessMedia(www.springer.com) Contents PI3K:FromtheBenchtotheClinicandBack .............................. 1 BartVanhaesebroeck,PeterK.Vogt,andChristianRommel OncogenicMutationsofPIK3CAinHumanCancers ..................... 21 YardenaSamuelsandToddWaldman StructuralEffectsofOncogenicPI3KaMutations ......................... 43 SandraB.Gabelli,Chuan-HsiangHuang,DianaMandelker, OlegSchmidt-Kittler,BertVogelstein,andL.MarioAmzel ComparingtheRolesofthep110aandp110bIsoforms ofPI3KinSignalingandCancer ............................................ 55 NinaIlic´ andThomasM.Roberts Phosphatidylinositol3-Kinase:TheOncoprotein ........................... 79 PeterK.Vogt,JonathanR.Hart,MarcoGymnopoulos,HaoJiang, SohyeKang,AndreasG.Bader,LiZhao,andAdamDenley AKTSignalinginPhysiologyandDisease ................................. 105 KrishnaM.VasudevanandLeviA.Garraway FaithfullModelingofPTENLossDrivenDiseasesintheMouse ........ 135 CaterinaNardella,ArkaitzCarracedo,LeonardoSalmena, andPierPaoloPandolfi PI3KasaTargetforTherapyinHaematologicalMalignancies ......... 169 AsimKhwaja ClinicalDevelopmentofPhosphatidylinositol-3Kinase PathwayInhibitors ........................................................... 189 CarlosL.Arteaga v vi Contents FromtheBenchtotheBedSide:PI3KPathwayInhibitorsinClinical Development .................................................................. 209 Saveur-MichelMaira,PeterFinan,andCarlosGarcia-Echeverria NewInhibitorsofthePI3K-Akt-mTORPathway:InsightsintomTOR SignalingfromaNewGenerationofTorKinaseDomainInhibitors (TORKinibs) .................................................................. 241 MorrisE.FeldmanandKevanM.Shokat SmallMoleculeInhibitorsofthePI3-KinaseFamily ...................... 263 ZacharyA.Knight TargetingtheRTK-PI3K-mTORAxisinMalignantGlioma: OvercomingResistance ...................................................... 279 Qi-WenFanandWilliamA.Weiss Index .......................................................................... 297 Contributors L. Mario Amzel Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA, [email protected] CarlosL.Arteaga DepartmentofMedicine,VanderbiltUniversitySchoolof Medicine, Nashville, TN, USA and Department of Cancer Biology, Breast CancerResearchProgram,Vanderbilt-IngramComprehensiveCancerCenter, Vanderbilt University School of Medicine, Nashville, TN, USA and Division of Oncology, VUMC, 2220 Pierce Avenue, 777 PRB, Nashville, TN 37232- 6307, USA, [email protected] Andreas G. Bader Mirna Therapeutics Inc. 2150 Woodward, Suite 100, Austin, TX 78744, USA ArkaitzCarracedo CancerGeneticsProgram,BethIsraelDeaconessCancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA Adam Denley Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA Qi-Wen Fan Departments of Neurology, University of California, 1450 3rd St, MC0520, San Francisco, CA 94158-9001, USA Morris E. Feldman Howard Hughes Medical Institute, UC San Francisco, 600 16th St., Genentech Hall, San Francisco, CA 94158, USA and Depart- ment of Cellular and Molecular Pharmacology, UC San Francisco, 600 16th St., Genentech Hall, San Francisco, CA 94158, USA vii viii Contributors Peter Finan Novartis Institutes for Biomedical Research, Cambridge, USA Sandra B. Gabelli Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA, [email protected] Carlos Garcia-Echeverria Oncology Drug Discovery, Novartis Institutes for Biomedical Research, 13, quai Jules Guesde, 94403 Vitry-sur-Seine Cedex, France, [email protected] Levi A. Garraway Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA and Department of Medicine, Brigham and’Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA and The Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA, [email protected] MarcoGymnopoulos DepartmentofMolecularandExperimentalMedicine, TheScrippsResearchInstitute,10550NorthTorreyPinesRoad,LaJolla,CA 92037, USA Jonathan R. Hart Department of Molecular and Experimental Medicine, TheScrippsResearchInstitute,10550NorthTorreyPinesRoad,LaJolla,CA 92037, USA Chuan-HsiangHuang DepartmentofBiophysicsandBiophysicalChemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA and Department of Cell Biology and Anatomy, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA Nina Ilic´ Dana-Farber Cancer Institute, Department of Cancer Biology, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA and DepartmentofPathology,HarvardMedicalSchool,Boston,MA02115,USA Hao Jiang Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA Sohye Kang Amgen,OneAmgenCenterDrive,ThousandOaks, CA91320, USA AsimKhwaja UCLCancerInstitute,UniversityCollegeLondon,72Huntley Street, London WC1E 6BT, UK, [email protected] Contributors ix Zachary A. Knight The Rockefeller University, 1230 York Ave, New York, NY 10065, USA, [email protected] Saveur-Michel Maira Oncology Drug Discovery, Novartis Institutes for Biomedical Research, 13, quai Jules Guesde, 94403 Vitry-sur-Seine Cedex, France DianaMandelker LudwigCenterforCancerGeneticsandTherapeuticsand TheHowardHughes MedicalInstituteattheJohnsHopkinsKimmelCancer Center, Baltimore, MD 21231, USA Caterina Nardella Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Preclinical Murine Pharma- cogenetics Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA Pier Paolo Pandolfi Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA, [email protected] Thomas M. Roberts Dana-Farber Cancer Institute, Department of Cancer Biology,HarvardMedicalSchool,44BinneyStreet,Boston,MA02115,USA and Department of Pathology, Harvard Medical School, Boston, MA 02115, USA, [email protected] ChristianRommel IntellikineInc.,10931NorthTorreyPinesRoad,LaJolla, CA 92037, USA LeonardoSalmena CancerGeneticsProgram,BethIsraelDeaconessCancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA Yardena Samuels Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA, [email protected] Oleg Schmidt-Kittler Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA KevanM.Shokat HowardHughesMedicalInstitute,UCSanFrancisco,600 16thSt.,GenentechHall,SanFrancisco,CA94158,USAandDepartmentof