Mechanisms of Drug Resistance in Cancer Therapy PDF
Preview Mechanisms of Drug Resistance in Cancer Therapy
Handbook of Experimental Pharmacology 249 Mario Mandalà Emanuela Romano Editors Mechanisms of Drug Resistance in Cancer Therapy Handbook of Experimental Pharmacology Volume 249 Editor-in-Chief J.E.Barrett,Philadelphia EditorialBoard V.Flockerzi,Homburg M.A.Frohman,StonyBrook,NY P.Geppetti,Florence F.B.Hofmann,München M.C.Michel,Mainz C.P.Page,London W.Rosenthal,Jena K.Wang,Qingdao Moreinformationaboutthisseriesathttp://www.springer.com/series/164 (cid:129) Mario Mandalà Emanuela Romano Editors Mechanisms of Drug Resistance in Cancer Therapy Editors MarioMandalà EmanuelaRomano DepartmentofOncologyandHematology DepartmentofOncology,INSERM Res PapaGiovanniXXIIIHospital Unit932 Bergamo,Italy InstitutCurie ParisCedex05,France ISSN0171-2004 ISSN1865-0325 (electronic) HandbookofExperimentalPharmacology ISBN978-3-030-10506-8 ISBN978-3-030-10507-5 (eBook) https://doi.org/10.1007/978-3-030-10507-5 LibraryofCongressControlNumber:2018966536 #SpringerNatureSwitzerlandAG2018 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartofthe materialisconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation, broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmissionorinformation storageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilarmethodology nowknownorhereafterdeveloped. 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ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSwitzerlandAG Theregisteredcompanyaddressis:Gewerbestrasse11,6330Cham,Switzerland Preface The remarkable advances in precision medicine and the development of targeted cancertreatmentshavegeneratedsignificantoptimismbasedontheassumptionthat abetterknowledgeofgeneticormolecularfeaturessustainingcancergrowthcould determine long-term control of many types of cancer and potentially cure the majority of patients. After several years of basic and translational research, the oncology community has tempered this optimism by the recognition that in only a minority of patients cure can be achieved by innovative strategies such as targeted therapies, immunotherapy and cytotoxic agents. In the vast majority of cancer patients, cancer wins the battle, and the reason for this failure is drug resistance. Ultimately, advanced cancer patients die because some or all of their tumour cells exhibit or develop resistance to available therapeutic strategies. The challenge of drug resistance therefore represents an important barrier that hinders the ultimate goalofcureoratleastlong-termcontrolofcancer. Asacorollaryofthis,responseratesinthesettingoftumourprogression/relapse are dismal. Despite the considerable importance of drug resistance to cancer therapies, our understanding of their biological mechanisms – and plausible thera- peuticavenuestointerceptthem–remainshighlyincomplete. Knowledge of specific resistance mechanisms can inform novel therapeutic approachestocounterthisphenomenon,andimprovementofourunderstandingof key driver genes could guide new therapeutics approaches capable of eliciting meaningfultumourresponsesinpatientswithadvancedmalignancies. As previously reported with chemotherapy, it is reasonable to suppose that a combinationofmultipletargetedtherapiesandimmunotherapystrategiesaswellas plannedsequenceoftreatmentswillbenecessarytoeffectivelypreventand/ortreat drug-resistant cancers. The potential number of therapeutic combinations is immense; thus, new preclinical paradigms are needed to prioritize high-yield combinations and define the genetic or molecular contexts in which they would most likely be efficacious. To improve outcome of patients a strict collaboration betweenacademiaandindustrywillbeneededsothattheappropriateresourcesand innovation may be brought to bear on this challenge. The goal to achieve durable control of many cancer subtypes will likely require dedicated, multidisciplinary teams of preclinical and clinical experts that work together guided by rigorous translationalandanalyticalscience. v vi Preface With the increasing armamentarium of anticancer agents and the advent of powerful high-throughput screening techniques, there are now unprecedented opportunities to understand and overcome drug resistance through the clinical assessmentofrational therapeuticdrugcombinations andtheuseofpredictive and prognosticbiomarkerstoenablepatientstratificationandtailortreatments. Themainaimofthisbookistooffertothereaders anupdatedoverviewonthe possiblereasonsoffailureofnewandpromisingtherapeuticopportunities. The first part of the book covers the basic mechanisms of such hot topics. The otherchapterscoverspecificpathwaysofresistancethatfromtheknowledgeofbasic mechanisms translate this information in clinical routine or in translational clinical research. Readers will discover diverse perspectives of the contributing authors (such as basicscientists,clinicalpharmacologistsandclinicians)andextensivediscussionsof issuesincludingpharmacodynamicandpharmacokineticmechanismsofresistance, alterationsinthedrugtarget,activationofprosurvivalpathways,ineffectiveinduc- tionofcelldeathandplasticityofmicroenvironment. This book will be of interest to scholars and researchers, biologists, pharmacologists,medicaloncologists,haematologistsandimmunologists. Bergamo,Italy MarioMandalà ParisCedex05,France EmanuelaRomano Contents MolecularandPharmacologicalMechanismsofDrugResistance: AnEvolvingParadigm. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 BenedettaColmegna,LaviniaMorosi,andMaurizioD’Incalci MajorPhysiologicalSignalingPathwaysintheRegulation ofCellProliferationandSurvival. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 HuifangTangandGongdaXue Immune-MediatedandHypoxia-RegulatedPrograms:Accomplices inResistancetoAnti-angiogenicTherapies. . . . . . . . . . . . . . . . . . . . . . . 31 DiegoO.Croci,SantiagoP.Mendez-Huergo,JuanP.Cerliani, andGabrielA.Rabinovich MechanismsofResistancetoTargetTherapiesinNon-smallCellLung Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 FrancescoFacchinetti,ClaudiaProto,RobertaMinari,MarinaGarassino, andMarcelloTiseo MechanismsofDrugResistanceinMelanoma. . . . . . . . . . . . . . . . . . . . 91 MatthewWinderandAmayaVirós MechanismsofResistancetoImmuneCheckpointAntibodies. . . . . . . . 109 RodrigoN.Ramos,ElianePiaggio,andEmanuelaRomano ImmunotoleranceasaMechanismofResistancetoTargetedTherapies inMelanoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 MarioMandalàandDanielaMassi PlasticityofResistanceandSensitivitytoAnti-EpidermalGrowth FactorReceptorInhibitorsinMetastaticColorectalCancer. . . . . . . . . . 145 AndreaSartore-BianchiandSalvatoreSiena TargetingDNARepair. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 GiuseppeCurigliano ResistancetoHormonalTherapyinProstateCancer. . . . . . . . . . . . . . . 181 AlfredoBerrutiandAlbertoDallaVolta vii viii Contents MechanismofResistanceinGastrointestinalStromalTumors. . . . . . . . 195 E.Tamborini MechanismsofResistancetoTargetedTherapiesinChronic LymphocyticLeukemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 FrancescaArrugaandSilviaDeaglio MechanismsofResistancetoTargetedTherapiesinChronicMyeloid Leukemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 FedericoLussana,TamaraIntermesoli,PaolaStefanoni, andAlessandroRambaldi MechanismsofResistanceinMultipleMyeloma. . . . . . . . . . . . . . . . . . . 251 AthanasiosPapadasandFotisAsimakopoulos CancerEvolutionastheNewFrontierofPrecisionMedicine. . . . . . . . . 289 GiuseppeCurigliano Molecular and Pharmacological Mechanisms of Drug Resistance: An Evolving Paradigm Benedetta Colmegna, Lavinia Morosi, and Maurizio D’Incalci Contents 1 Introduction................................................................................... 2 2 CellularMechanismofMultidrugResistance............................................... 4 2.1 DrugActivationandInactivation...................................................... 4 2.2 ExpressionofDrugEffluxPumps..................................................... 5 2.3 DNADamageRepair................................................................... 7 2.4 DeregulationofApoptosis............................................................. 8 2.5 AlterationofDrugTarget.............................................................. 9 3 Conclusion.................................................................................... 10 References........................................................................................ 11 Abstract The high heterogeneity and genomic instability of malignant tumors explains why even responsive tumors contain cell clones that are resistant for many possible mechanisms involving intracellular drug inactivation, low uptake or high efflux of anticancer drugs from cancer cells, qualitative or quantitative changes in the drug target. Many tumors, however, are resistant because of insufficient exposure to anticancer drugs, due to pharmacokinetic reasons and inefficient and heterogeneous tumor drug distribution, related to a deficient vascularization and high interstitial pressure. Finally, resistance can be related totheactivationofanti-apoptoticandcellsurvivalpathwaysbycancercellsand oftenenhancedbytumormicroenvironment. B.Colmegna•L.Morosi•M.D’Incalci(*) DepartmentofOncology,IRCCS‘MarioNegri’,InstituteforPharmacologicalResearch,20145 Milan,Italy e-mail:[email protected] #SpringerInternationalPublishingAG2017 1 M.Mandala`,E.Romano(eds.),MechanismsofDrugResistanceinCancerTherapy, HandbookofExperimentalPharmacology249,DOI10.1007/164_2017_20
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