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dc.contributor.authorCosta, Daniel Botelho
dc.contributor.authorHalmos, Balázs
dc.contributor.authorKumar, Amit
dc.contributor.authorSchumer, Susan T
dc.contributor.authorHuberman, Mark Stephen
dc.contributor.authorBoggon, Titus J
dc.contributor.authorTenen, Daniel Geoffrey
dc.contributor.authorKobayashi, Susumu
dc.date.accessioned2011-04-08T14:47:14Z
dc.date.issued2007
dc.identifier.citationCosta, Daniel B., Balázs Halmos, Amit Kumar, Susan T. Schumer, Mark S. Huberman, Titus J. Boggon, Daniel G. Tenen, and Susumu Kobayashi. 2007. BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Medicine 4, no. 10: e315.en_US
dc.identifier.issn1549-1277en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:4817340
dc.description.abstractBackground: Epidermal growth factor receptor (EGFR) mutations are present in the majority of patients with non-small cell lung cancer (NSCLC) responsive to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. These EGFR-dependent tumors eventually become TKI resistant, and the common secondary T790M mutation accounts for half the tumors with acquired resistance to gefitinib. However, the key proapoptotic proteins involved in TKI-induced cell death and other secondary mutations involved in resistance remain unclear. The objective of this study was to identify the mechanism of EGFR TKI-induced apoptosis and secondary resistant mutations that affect this process. Methods and Findings: To study TKI-induced cell death and mechanisms of resistance, we used lung cancer cell lines (with or without EGFR mutations), Ba/F3 cells stably transfected with EGFR mutation constructs, and tumor samples from a gefitinib-resistant patient. Here we show that up-regulation of the BH3-only polypeptide BIM (also known as BCL2-like 11) correlated with gefitinib-induced apoptosis in gefitinib-sensitive EGFR-mutant lung cancer cells. The T790M mutation blocked gefitinib-induced up-regulation of BIM and apoptosis. This blockade was overcome by the irreversible TKI CL-387,785. Knockdown of BIM by small interfering RNA was able to attenuate apoptosis induced by EGFR TKIs. Furthermore, from a gefitinib-resistant patient carrying the activating L858R mutation, we identified a novel secondary resistant mutation, L747S in cis to the activating mutation, which attenuated the up-regulation of BIM and reduced apoptosis. Conclusions: Our results provide evidence that BIM is involved in TKI-induced apoptosis in sensitive EGFRmutant cells and that both attenuation of the up-regulation of BIM and resistance to gefitinibinduced apoptosis are seen in models that contain the common EGFR T790M and the novel L747S secondary resistance mutations. These findings also suggest that induction of BIM may have a role in the treatment of TKI-resistant tumors.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi://10.1371/journal.pmed.0040315en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2043012/pdf/en_US
dc.relation.hasversionwww.plosmedicine.orgen_US
dash.licenseLAA
dc.subjectcell biologyen_US
dc.subjectoncologyen_US
dc.subjectpharmacologyen_US
dc.subjectrespiratory medicineen_US
dc.subjectdrugs and adverse drug reactionsen_US
dc.subjectcancer: lungen_US
dc.titleBIM Mediates EGFR Tyrosine Kinase Inhibitor-Induced Apoptosis in Lung Cancers with Oncogenic EGFR Mutationsen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS Medicineen_US
dash.depositing.authorTenen, Daniel Geoffrey
dc.date.available2011-04-08T14:47:14Z
dash.affiliation.otherHMS^Medicine- Beth Israel-Deaconessen_US
dash.affiliation.otherHMS^Medicine- Beth Israel-Deaconessen_US
dc.identifier.doi10.1371/journal.pmed.0040315*
dash.contributor.affiliatedHuberman, Mark Stephen
dash.contributor.affiliatedKobayashi, Susumu
dash.contributor.affiliatedCosta, Daniel
dash.contributor.affiliatedTenen, Daniel


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