BIM Mediates EGFR Tyrosine Kinase Inhibitor-Induced Apoptosis in Lung Cancers with Oncogenic EGFR Mutations

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BIM Mediates EGFR Tyrosine Kinase Inhibitor-Induced Apoptosis in Lung Cancers with Oncogenic EGFR Mutations

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dc.contributor.author Halmos, Balázs
dc.contributor.author Kumar, Amit
dc.contributor.author Schumer, Susan T
dc.contributor.author Boggon, Titus J
dc.contributor.author Costa, Daniel Botelho
dc.contributor.author Huberman, Mark Stephen
dc.contributor.author Tenen, Daniel Geoffrey
dc.contributor.author Kobayashi, Susumu
dc.date.accessioned 2011-04-08T14:47:14Z
dc.date.issued 2007
dc.identifier.citation Costa, 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.issn 1549-1277 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:4817340
dc.description.abstract Background: 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.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi://10.1371/journal.pmed.0040315 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2043012/pdf/ en_US
dc.relation.hasversion www.plosmedicine.org en_US
dash.license LAA
dc.subject cell biology en_US
dc.subject oncology en_US
dc.subject pharmacology en_US
dc.subject respiratory medicine en_US
dc.subject drugs and adverse drug reactions en_US
dc.subject cancer: lung en_US
dc.title BIM Mediates EGFR Tyrosine Kinase Inhibitor-Induced Apoptosis in Lung Cancers with Oncogenic EGFR Mutations en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS Medicine en_US
dash.depositing.author Tenen, Daniel Geoffrey
dc.date.available 2011-04-08T14:47:14Z
dash.affiliation.other HMS^Medicine- Beth Israel-Deaconess en_US
dash.affiliation.other HMS^Medicine- Beth Israel-Deaconess en_US

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