Antitumor Activity of Sorafenib in Human Cancer Cell Lines with Acquired Resistance to EGFR and VEGFR Tyrosine Kinase Inhibitors 英文参考文献.docVIP
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Antitumor Activity of Sorafenib in Human Cancer Cell Lines with Acquired Resistance to EGFR and VEGFR Tyrosine Kinase Inhibitors 英文参考文献
AntitumorActivityofSorafenibinHumanCancerCell
LineswithAcquiredResistancetoEGFRandVEGFR
TyrosineKinaseInhibitors
FlorianaMorgillo*,ErikaMartinelli,TeresaTroiani,MicheleOrditura,FerdinandoDeVita,Fortunato
Ciardiello
DivisionofMedicalOncology,DepartmentofClinicalandExperimentalMedicineandSurgeryF.MagrassieA.LanzaraSecondUniversityofNaples,Naples,Italy
Abstract
Treatmentofnonsmallcelllungcancer(NSCLC)andcolorectalcancer(CRC)havesubstantiallychangedinthelastyears
withtheintroductionofepidermalgrowthfactorreceptor(EGFR)inhibitorsintheclinicalpractice.Theunderstandingof
mechanismswhichregulatecellssensitivitytothesedrugsisnecessaryfortheiroptimaluse. Aninvitromodelofacquired
resistancetotwotyrosinekinaseinhibitors(TKI)targetingtheEGFR,erlotinibandgefitinib,andtoaTKItargetingEGFRand
VEGFR,vandetanib,wasdevelopedbycontinuouslytreatingthehumanNSCLCcelllineCALU-3andthehumanCRCcellline
HCT116withescalating doses ofeachdrug.MTT,western blot analysis,migration, invasionandanchorage-independent
colonyformingassayswereconductedinvitroandexperimentswithestablishedxenograftsinathymicnudemicewere
performedinvivoinsensitive,wildtype(WT)andTKI-resistantCALU-3andHCT116celllines. AscomparedtoWTCALU-3
and HCT116 human cancer cells, TKI-resistant cell lines showed a significant increase in the levels of activated,
phosphorylatedAKT,MAPK,andofsurvivin.ConsideringtheroleofRASandRAFasdownstreamsignalsofboththeEGFR
and VEGFR pathways, we treated resistant cells with sorafenib, an inhibitor of C-RAF, B-RAF, c-KIT, FLT-3, RET, VEGFR-2,
VEGFR-3,andPDGFR-b.SorafenibreducedtheactivationofMEKandMAPKandcausedaninhibitionofcellproliferation,
invasion,migration,anchorage-independentgrowthinvitroandoftumorgrowthinvivoofallTKI-resistantCALU-3and
HCT116 cell lines. These data suggest that resistance to EGFR inhibitors is predominantly driven by the RAS/RAF/MAPK
pathwayandcanbeovercamebytreatmentwithsorafenib.
Citation:MorgilloF,MartinelliE,TroianiT,OrdituraM,DeVitaF,etal.(2011)AntitumorAc
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