Kinase-Impaired BRAF Mutations in Lung Cancer Confer Sensitivity to Dasatinib

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dc.contributor.authorSen, Banibrata
dc.contributor.authorPeng, Shaohua
dc.contributor.authorTang, Ximing
dc.contributor.authorErickson, Heidi S.
dc.contributor.authorGalindo, Hector
dc.contributor.authorMazumdar, Tuhina
dc.contributor.authorStewart, David J.
dc.contributor.authorWistuba, Ignacio
dc.contributor.authorJohnson, Faye M.
dc.date.accessioned2024-01-10T12:39:55Z
dc.date.available2024-01-10T12:39:55Z
dc.date.issued2012
dc.description.abstractDuring a clinical trial of the tyrosine kinase inhibitor dasatinib for advanced non-small cell lung cancer (NSCLC), one patient responded dramatically and remains cancer-free 4 years later. A comprehensive analysis of his tumor revealed a previously undescribed, kinase-inactivating BRAF mutation ((Y472C)BRAF); no inactivating BRAF mutations were found in the nonresponding tumors taken from other patients. Cells transfected with (Y472C)BRAF exhibited CRAF, MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase), and ERK (extracellular signal-regulated kinase) activation-characteristics identical to signaling changes that occur with previously known kinase-inactivating BRAF mutants. Dasatinib selectively induced senescence in NSCLC cells with inactivating BRAF mutations. Transfection of other NSCLC cells with these BRAF mutations also increased these cells' dasatinib sensitivity, whereas transfection with an activating BRAF mutation led to their increased dasatinib resistance. The sensitivity induced by (Y472C)BRAF was reversed by the introduction of a BRAF mutation that impairs RAF dimerization. Dasatinib inhibited CRAF modestly, but concurrently induced RAF dimerization, resulting in ERK activation in NSCLC cells with kinase-inactivating BRAF mutations. The sensitivity of NSCLC with kinase-impaired BRAF to dasatinib suggested synthetic lethality of BRAF and an unknown dasatinib target. Inhibiting BRAF in NSCLC cells expressing wild-type BRAF likewise enhanced these cells' dasatinib sensitivity. Thus, the patient's BRAF mutation was likely responsible for his tumor's marked response to dasatinib, suggesting that tumors bearing kinase-impaired BRAF mutations may be exquisitely sensitive to dasatinib. Moreover, the potential synthetic lethality of combination therapy including dasatinib and BRAF inhibitors may lead to additional therapeutic options against cancers with wild-type BRAF.
dc.description.funderNational Cancer Institute
dc.description.funderUniversity of Texas Lung SPORE
dc.description.funderBristol-Myers Squibb
dc.description.funderNIH through M. D. Anderson's Cancer Center
dc.description.funderAlign2Action Inc.
dc.description.funderBridger Capital LLC
dc.description.funderEaston Associates
dc.description.funderTrinity Partners LLC
dc.description.funderWarburg Pincus LLC
dc.description.funderAstraZeneca Taiwan
dc.description.funderNATIONAL CANCER INSTITUTE
dc.fechaingreso.objetodigital2024-05-14
dc.format.extent10 páginas
dc.fuente.origenWOS
dc.identifier.doi10.1126/scitranslmed.3003513
dc.identifier.eissn1946-6242
dc.identifier.issn1946-6234
dc.identifier.pubmedidMEDLINE:22649091
dc.identifier.urihttps://doi.org/10.1126/scitranslmed.3003513
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/77249
dc.identifier.wosidWOS:000304865400005
dc.information.autorucMedicina;Galindo H ;S/I;18813
dc.issue.numero136
dc.language.isoen
dc.nota.accesocontenido parcial
dc.publisherAMER ASSOC ADVANCEMENT SCIENCE
dc.revistaSCIENCE TRANSLATIONAL MEDICINE
dc.rightsacceso restringido
dc.subjectB-RAF
dc.subjectCELLS
dc.subjectACTIVATION
dc.subjectINHIBITORS
dc.subjectMELANOMA
dc.subjectCRAF
dc.subjectAPOPTOSIS
dc.subjectTUMORS
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleKinase-Impaired BRAF Mutations in Lung Cancer Confer Sensitivity to Dasatinib
dc.typeartículo
dc.volumen4
sipa.codpersvinculados18813
sipa.indexWOS
sipa.indexScopus
sipa.trazabilidadCarga SIPA;09-01-2024
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