Multiplexed deep sequencing analysis of ALK kinase domain identifies resistance mutations in relapsed patients following crizotinib treatment

Genomics

Shibing Deng¹  Paul Lira¹  Pamela Vizcarra¹  Myung-Ju Ahn¹  Joan Q. Cao¹  Mao Mao¹  Dong-Wan Kim¹  Steffan N. Ho¹  Jong-mu Sun¹  Keunchil Park¹  James G. Christensen¹  Jin Seok Ahn¹  Nathan V. Lee¹  Donghui Huang¹  Tae Min Kim¹  Athanasios Kotsakis¹ 

关键词: Crizotinib;    Resistance;    Mutation;    Deep sequencing;   

DOI  :  10.1016/j.ygeno.2013.02.006

学科分类：医学（综合）

来源: Academic Press

【 摘 要 】

TherecentlyapprovedALKkinaseinhibitorcrizotinibhasdemonstratedsuccessfultreatmentofmetastaticandlatestageALKfusionpositivenon-smallcelllungcancer(NSCLC).However,themediandurationofclinicalbenefitis~#xA0;10ndash;11#xA0;monthsduetotheemergenceofmultipleandsimultaneousresistancemechanismsinthesetumors.MutationsintheALKkinasedomainconferresistancetocrizotinibinaboutone-thirdofthesepatients.WedevelopedamultiplexdeepsequencingmethodusingsemiconductorsequencingtechnologytoquicklydetectresistancemutationswithintheALKkinasedomainfromtumorbiopsies.Byapplyingabase-pairspecificerror-weightedmutationcallingalgorithm(BASCA)thatwedevelopedforthisassay,genomicDNAanalysisfromthirteenrelapsedpatientsrevealedthreeknowncrizotinibresistancemutations,C1156Y,L1196MandG1269A.OurassaydemonstratesrobustandsensitivedetectionofALKkinasemutationsinNSCLCtumorsamplesandaidsintheelucidationofresistancemechanismspertinenttotheclinicalsetting.

【 授权许可】

Unknown   

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