Cancer Signaling: from molecular biology to targeted therapy

357 Pages·2017·9.253 MB·English

by  Müller, Oliver, Stocking, Carol, Wagener, Christoph

ChristophWagener,
CarolStocking,
andOliverMüller
CancerSignaling

ChristophWagener,CarolStocking,andOliverMüller
Cancer Signaling
FromMolecularBiologytoTargetedTherapy
Authors AllbookspublishedbyWiley-VCH
arecarefullyproduced.Nevertheless,
ProfessorDr.ChristophWagener authors,editors,andpublisherdonot
UniversityMedicalCenterHamburg- warranttheinformationcontainedin
Eppendorf thesebooks,includingthisbook,to
Martinistr.52 befreeoferrors.Readersareadvised
20251Hamburg tokeepinmindthatstatements,data,
Germany illustrations,proceduraldetailsorother
itemsmayinadvertentlybeinaccurate.
Dr.CarolStocking
Heinrich-Pette-Institute LibraryofCongressCardNo.:appliedfor
LeibnizInstituteofExperimental
Virology BritishLibraryCataloguing-in-Publication
Martinistr.52 Data
20251Hamburg Acataloguerecordforthisbookis
Germany availablefromtheBritishLibrary.
ProfessorDr.Dr.OliverMüller Bibliographicinformationpublishedbythe
UniversityofAppliedSciences DeutscheNationalbibliothek
Kaiserslautern TheDeutscheNationalbibliothek
CampusZweibrücken liststhispublicationintheDeutsche
Amerikastr.1 Nationalbibliografie;detailed
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Germany Internetat<http://dnb.d-nb.de>.
Cover
©2017Wiley-VCHVerlagGmbH&Co.
Inabreastcancerspecimen
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prolongandsavelives.

VII
Contents
Preface XV
Acknowledgments XXI
ListofAbbreviations XXIII
AbouttheCompanionWebsite XXIX
1 GeneralAspectsofSignalTransductionandCancerTherapy 1
1.1 GeneralPrinciplesofSignalTransduction 2
1.1.1 BiologicalSignalshavetobeProcessed 2
1.1.2 WhatisaSignalTransductionPathway? 2
1.1.3 MechanismsofDirectSignalTransduction 4
1.1.4 TheInteractomeGivesInsightintotheSignalingNetwork 5
1.1.5 ProteinDomainsforProtein–ProteinInteractionandSignal
Transduction 6
1.1.6 FunctionsofMutatedProteinsinTumorCells 8
1.2 DrugsagainstCancer 10
1.2.1 TermsandDefinitions 10
1.2.2 TheStepsfromaNormalCelltoaTumor 10
1.2.3 InterferenceLevelsofTherapeuticDrugs 11
1.2.4 DrugsAttackingtheWholeCell 12
1.2.4.1 DNAAlkylatingDrugs 13
1.2.5 Process-BlockingDrugs 14
1.2.5.1 DrugsBlockingSynthesisofDNAandRNA 14
1.2.5.2 DrugsBlockingtheSynthesisofDNAandRNAPrecursor
Molecules 15
1.2.5.3 DrugsBlockingDynamicsofMicrotubules 16
1.2.6 InnovativeMolecule-InterferingDrugs 18
1.2.7 Fast-DividingNormalCellsandSlowlyDividingTumorCells:Side
EffectsandRelapse 19
1.2.8 DrugResistance 19
1.2.8.1 DrugsCircumventingResistance 19
1.3 Outlook 20
References 21
VIII Contents
2 TumorCellHeterogeneityandResistancetoTargetedTherapy 23
2.1 TheGeneticBasisofTumorigenesis 24
2.2 ClonalHeterogeneity 24
2.2.1 ClonalOriginofTumors 24
2.2.2 ClonalEvolution 26
2.2.3 TheTimeCourseofClonalEvolution 30
2.2.4 ClonalEvolutionandResistancetoTherapy 32
2.2.5 TargetingEssentialDrivers(DriverAddiction) 34
2.2.6 ResistancebyAlternativePathwayActivation 36
2.2.7 OvercomingResistancebyCombinatorialTherapies 36
2.3 TumorStemCellsandTumorCellHierarchies 37
2.4 EpigeneticsandPhenotypicPlasticity 40
2.5 Microenvironment 42
2.6 Outlook 43
References 44
3 CellCycleofTumorCells 47
3.1 PropertiesofTumorCells 48
3.1.1 DifferencesbetweenTumorCellsandNormalCellsIn
vitro 49
3.1.2 RegulationofCellNumber 49
3.2 TheCellCycle 50
3.2.1 Checkpoints 51
3.2.2 Cyclins 52
3.2.3 Cyclin-DependentKinases(CDKs) 53
3.2.4 TheRetinoblastoma-AssociatedProteinRbasRegulatorofthe
CellCycle 54
3.2.5 InhibitorsofCDKs 54
3.2.6 CheckpointsandDNAIntegrity 55
3.2.7 TheRepairMechanismDependsontheCellCyclePhase 57
3.2.8 Tumor-RelevantProteinsintheCellCycle 57
3.3 TheCellCycleasTherapeuticTarget 58
3.3.1 SmallCompoundsInhibitingCell-Cycle-DependentKinasesas
AnticancerDrugs 59
3.4 Outlook 60
References 61
4 CellAgingandCellDeath 63
4.1 ACell’sJourneythroughLife 64
4.2 CellularAgingandSenescence 64
4.2.1 ReplicativeSenescence 65
4.2.2 ShorteningofChromosomalTelomeresduringReplication 67
4.2.3 ChromosomalTelomeres 67
4.2.4 Telomerase 69
4.2.5 AnimalModels 72