Differential Sensitivity of ERBB2 Kinase Domain Mutations towards Lapatinib 英文参考文献.docVIP

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Differential Sensitivity of ERBB2 Kinase Domain Mutations towards Lapatinib 英文参考文献.doc

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Differential Sensitivity of ERBB2 Kinase Domain Mutations towards Lapatinib 英文参考文献

DifferentialSensitivityofERBB2KinaseDomain MutationstowardsLapatinib RamaKrishnaKancha1,NikolasvonBubnoff1,NatalieBartosch1,ChristianPeschel1,RichardA.Engh2, JustusDuyster1* 1DepartmentofInternalMedicineIII,TechnicalUniversityofMunich,Munich,Germany,2NORSTRUCT,DepartmentofChemistry,UniversityofTroms?,Troms?,Norway Abstract Background: Overexpression of the ERBB2 kinase is observed in about one-third of breast cancer patients and the dual ERBB1/ERBB2kinaseinhibitorlapatinibwasrecentlyapprovedforthetreatmentofadvancedERBB2-positivebreastcancer. MutationsintheERBB2receptorhaverecentlybeenreportedinbreastcanceratdiagnosisandalsoingastric,colorectaland lungcancer.Thesemutationsmayhaveanimpactontheclinicalresponsesachievedwithlapatinibinbreastcancerand mayalsohaveapotentialimpactontheuseoflapatinibinothersolidcancers.However,thesensitivityoflapatinibtowards clinicallyobservedERBB2mutationsisnotknown. Methodology/PrincipalFindings:Weclonedapanelof8clinicallyobservedERBB2mutations,establishedstablecelllines andcharacterizedtheirsensitivitytowardslapatinibandalternativeERBB2inhibitors.Bothlapatinib-sensitiveandlapatinib- resistant ERBB2 mutations were observed. Interestingly, we were able to generate lapatinib resistance mutations in wt- ERBB2cellsincubatedwithlapatinibforprolongedperiodsoftime.Thisindicatesthattheseresistancemutationsmayalso cause secondary resistance in lapatinib-treated patients. Lapatinib-resistant ERBB2 mutations were found to be highly resistanttowardsAEE788treatmentbutremainedsensitivetowardsthedualirreversibleinhibitorsCL-387785andWZ-4002. Conclusions/Significance:PatientsharbouringcertainERBB2kinasedomainmutationsatdiagnosismaynotbenefitfrom lapatinib treatment. Moreover, secondary lapatinib resistance may develop due to kinase domain mutations. Irreversible ERBB2 inhibitors may offer alternative treatment options for breast cancer and other solid tumor patients harbouring lapatinib resistance mutations. In addition, these inhibitors may be of int