Table Of ContentCurrent 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.
ISBN978-3-540-77348-1
Vol.339:Spearman,Paul;Freed,EricO.(Eds.):
Vol.326:Reddy,AnireddyS.N;Golovkin,Maxim(Eds.): HIVInteractionswithHostCellProteins.2009.
Nuclearpre-mRNAprocessinginplants.2008. ISBN978-3-642-02174-9
ISBN978-3-540-76775-6
Vol.340:Saito,Takashi;Batista,FacundoD.(Eds.):
Vol.327:Manchester,Marianne;Steinmetz, ImmunologicalSynapse.2010.
NicoleF.(Eds.): ISBN978-3-642-03857-0
VirusesandNanotechnology.2008.
ISBN978-3-540-69376-5 Vol.341:Bruserud,Øystein(Ed.):
TheChemokineSysteminClinical
Vol.328:vanEtten,(Ed.): andExperimentalHematology.2010.
LesserKnownLargedsDNAViruses.2008. ISBN978-3-642-12638-3
ISBN978-3-540-68617-0
Vol.342:Arvin,AnnM.(Ed.):
Vol.329:Griffin,DianeE.; Varicella-zosterVirus.2010.
Oldstone,MichaelB.A.(Eds.):Measles.2009. ISBN978-3-642-12727-4
ISBN978-3-540-70522-2
Vol.343:Johnson,JohnE.(Ed.):
Vol.330:Griffin,DianeE.; CellEntrybyNon-EnvelopedViruses.2010.
Oldstone,MichaelB.A.(Eds.):Measles.2009. 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
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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
