TKIs治療中的耐藥突變及治療改進血液?腫瘤中心醫(yī)學檢驗科劉紅2014-05-21 WePromotetheApplications&InnovationsofLaboratoryWePromotetheApplications&InnovationsofLaboratoryHongxingLiu,etal.Dec.6.2010@Orlando,52 WePromotetheApplications&InnovationsofLaboratoryHongxingLiu,etal.Dec.6.2010@Orlando,52 WePromotetheApplications&InnovationsofLaboratoryWePromotetheApplications&InnovationsofLaboratoryABL1和BCR-BCR-ABL1蛋白的自我DanielW.SherbenouandBrianJ.DrukerJ.Clin.Invest.WePromotetheApplications&InnovationsofLaboratoryWeisbergE,etal.NatRevCancer.2007;7(5):345-WePromotetheApplications&InnovationsofLaboratory突變積累的內在原WePromotetheApplications&InnovationsofLaboratory IKZF1缺失、TP53突變的內在原能抑制CML腫瘤干細胞中的氧自由基和DNA的氧激酶活 氧自由 DNA氧化損*P<.01incomparisonwithuntreatednormalcells,**P<.05incomparisonwithuntreatedCML-CPandnormalcells,and***P<.05incomparisonwithuntreatedCML-CPWePromotetheApplications&InnovationsofLaboratoryCML/CML-CP小WePromotetheApplications&InnovationsofLaboratoryTKIs耐藥突變的WePromotetheApplications&InnovationsofLaboratoryWePromotetheApplications&InnovationsofLaboratoryTKIs耐藥突變的一般規(guī)激酶區(qū)突變是TKI耐藥的最導致藥 不管是否使用TKIs耐藥的突變是在TKIs耐藥其它IKZF1、TP53 突變也會發(fā)生并促使病情進同一突變對不同的TKIs耐藥程度有可作WePromotetheApplications&InnovationsofLaboratorySimonaSoverini,et MutationsinPhiladelphiahromosome–PositiveAcuteLymphoblasticLeukemia;FromtheImatinibtotheSecond-GenerationTyrosineKinaseInhibitorEraSimonaSoverini,etWePromotetheApplications&InnovationsofLaboratory換用二代TKIs 突變的動態(tài)變SimonaSoverini,etal.Blood.2013;122(9):1634-WePromotetheApplications&InnovationsofLaboratory耐藥突變動態(tài)變化的根源在于耐藥性WePromotetheApplications&InnovationsofLaboratory 檢測到的Imtinib耐藥突變（2010年統(tǒng)計HongxingLiu,etal.Dec.6.2010@Orlando,52 WePromotetheApplications&InnovationsofLaboratoryWePromotetheApplications&InnovationsofLaboratory應對耐藥或進一步提高療WePromotetheApplications&InnovationsofLaboratory從更成功的實踐中總結經CML:TKI+WePromotetheApplications&InnovationsofLaboratory二代、三代

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MayaKoren-Michowitz,etal.HematolOncol2012;30:200–5WePromotetheApplications&InnovationsofLaboratory二代TKI：結合力WeisbergE,etal.NatRevCancer.2007;7(5):345-WePromotetheApplications&InnovationsofLaboratory用Imatinib進行一線治療，但治療12個月仍未獲CCyR

WePromotetheApplications&InnovationsofLaboratoryDasatinibversusImatinibinPatientswithNewlyDiagnosedChronicMyeloidLeukemiainChronicPhase(CML-CP)intheTrial:18-MonthFollow-ShahNetProcASH WePromotetheApplications&InnovationsofLaboratoryWePromotetheApplications&InnovationsofLaboratory對部分耐藥突變有效，但對T315I突變仍肉豆OliverHantschelHaematologica.2012;97(2):WePromotetheApplications&InnovationsofLaboratoryWePromotetheApplications&InnovationsofLaboratoryTargetingBcr-AblbycombiningallostericwithATP-binding-siteinhibitors.ZhangJ,etal.Nature.2010Jan28;463(7280):501-6.WePromotetheApplications&InnovationsofLaboratoryWePromotetheApplications&InnovationsofLaboratory P<0.0001聯(lián)合應用Dasatinib、地和L-天門冬酰胺酶著延長致瘤小鼠的緩解Chemotherapeuticagentscircumventemergenceofdasatinib-resistantBCR-ABLkinasemutationsinaprecisemousemodelofPhiladelphiachromosome–positiveacutelymphoblasticleukemiaNidalBoulos,etal.Blood.2011;117(13):3585-95WePromotetheApplications&InnovationsofLaboratoryImatinib聯(lián)用長效干擾素獲得更好的ImatinibplusPeginterferonAlfa-2ainChronicMyeloidLeukemiaClaudePreudhomme,etNEnglJMed2010;363:2511-WePromotetheApplications&InnovationsofLaboratoryImatinib聯(lián)用干擾素更快獲得Theresponsetoimatinibandinterferon-αismorerapidthantheresponsetoimatinibalone:aretrospective ysisof495Philadelphia-positivechronicmyeloidleukemiapatientsinearlychronicphaseFrancescaPalandri,etal.WePromotetheApplications&InnovationsofLaboratoryImatinib+PegIFNaVS.

Theresponsetoimatinibandinterferon-αismorerapidthantheresponsetoimatinibalone:aretrospective ysisof495Philadelphia-positivechronicmyeloidleukemiapatientsinearlychronicphaseFrancescaPalandri,etWePromotetheApplications&InnovationsofLaboratoryVEGFplasmaVEGFlowVEGFplasmaInterferondecreasesVEGFlevelsinpatientswithchronicmyeloidleukemiatreatedwithimatinibL.Legrosa,etLeukemiaResearch38(2014)WePromotetheApplications&InnovationsofLaboratory遺傳多態(tài)性影響TKIsWePromotetheApplications&InnovationsofLaboratory加用BIM或BH3模擬劑，可能會有輔助的效AnnetteS.Gillings,etal.FEBSJournal276(2009)WePromotetheApplications&InnovationsofLaboratory遺傳缺失型/SNP與治療反應有具有BIM缺 AcommonBIMdeletionpolymorphismmediatesintrinsic kinaseinhibitorsincancerKingPanNg,etal.NatMed.2012;18(4):521-8WePromotetheApplications&InnovationsofLaboratory我們的資WePromotetheApplications&InnovationsofLaboratory耐藥突變檢測及報告WePromotetheApplications&InnovationsofLaboratoryTKI耐藥突變檢測的方法DanJones,etal.JMolDiagn2009,WePromotetheApplications&InnovationsofLaboratory 檢測方可以檢測所有的激酶區(qū)耐藥采用超保真聚合酶WePromotetheApplications&InnovationsofLaboratoryWePromotetheApplications&InnovationsofLaboratoryTKIs耐藥突變檢測及結果解還是 法最實盲目追求突變的檢測靈敏度沒有意義，5%耐藥突變是在動態(tài)演融 融 （可能）非耐藥的突變在報告時 或給予文字提突變對各種TKIs的耐藥資料可以隨 查WePromotetheApplica