BIM Mediates EGFR Tyrosine Kinase Inhibitor-Induced Apoptosis in Lung Cancers with Oncogenic EGFR Mutations
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{"title"=>"BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations", "type"=>"journal", "authors"=>[{"first_name"=>"Daniel B.", "last_name"=>"Costa", "scopus_author_id"=>"7201884715"}, {"first_name"=>"Balázs", "last_name"=>"Halmos", "scopus_author_id"=>"6602570477"}, {"first_name"=>"Amit", "last_name"=>"Kumar", "scopus_author_id"=>"56948859200"}, {"first_name"=>"Susan T.", "last_name"=>"Schumer", "scopus_author_id"=>"6506128119"}, {"first_name"=>"Mark S.", "last_name"=>"Huberman", "scopus_author_id"=>"7006261914"}, {"first_name"=>"Titus J.", "last_name"=>"Boggon", "scopus_author_id"=>"6603049539"}, {"first_name"=>"Daniel G.", "last_name"=>"Tenen", "scopus_author_id"=>"7006789087"}, {"first_name"=>"Susumu", "last_name"=>"Kobayashi", "scopus_author_id"=>"7405377760"}], "year"=>2007, "source"=>"PLoS Medicine", "identifiers"=>{"issn"=>"15491277", "isbn"=>"1549-1676 (Electronic)\\r1549-1277 (Linking)", "pmid"=>"17973572", "scopus"=>"2-s2.0-35648949422", "doi"=>"10.1371/journal.pmed.0040315", "sgr"=>"35648949422", "pui"=>"350035456"}, "id"=>"07b19614-4d30-31c0-840b-84a80f2ce6d2", "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 EGFR-mutant cells and that both attenuation of the up-regulation of BIM and resistance to gefitinib-induced 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.", "link"=>"http://www.mendeley.com/research/bim-mediates-egfr-tyrosine-kinase-inhibitorinduced-apoptosis-lung-cancers-oncogenic-egfr-mutations", "reader_count"=>104, "reader_count_by_academic_status"=>{"Unspecified"=>4, "Professor > Associate Professor"=>5, "Researcher"=>19, "Student > Doctoral Student"=>6, "Student > Ph. D. Student"=>27, "Student > Postgraduate"=>4, "Student > Master"=>15, "Other"=>8, "Student > Bachelor"=>10, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>4}, "reader_count_by_user_role"=>{"Unspecified"=>4, "Professor > Associate Professor"=>5, "Researcher"=>19, "Student > Doctoral Student"=>6, "Student > Ph. D. Student"=>27, "Student > Postgraduate"=>4, "Student > Master"=>15, "Other"=>8, "Student > Bachelor"=>10, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>4}, "reader_count_by_subject_area"=>{"Unspecified"=>7, "Engineering"=>2, "Biochemistry, Genetics and Molecular Biology"=>11, "Agricultural and Biological Sciences"=>42, "Medicine and Dentistry"=>31, "Pharmacology, Toxicology and Pharmaceutical Science"=>3, "Chemistry"=>6, "Psychology"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>2}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>31}, "Chemistry"=>{"Chemistry"=>6}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>42}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>11}, "Unspecified"=>{"Unspecified"=>7}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>3}}, "reader_count_by_country"=>{"Sweden"=>1, "United States"=>3, "Japan"=>4, "United Kingdom"=>1, "Germany"=>1, "India"=>1}, "group_count"=>3}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/943498"], "description"=>"<div><p>(A) Top: Annexin V apoptosis assay: Ba/F3 cells expressing L858R (LR), L858R-L747S #4 (LR-LS), or L858R-T790M (LR-TM) cells were grown in the absence or presence of gefitinib for 24 h. The data are reported as mean ± SD (<i>n</i> ≥ 3). Bottom: After the cells were treated for 3 h with increasing concentrations of gefitinib, lysates were collected and proteins analyzed by immunoblotting. BIM expression correlated with the amount of apoptosis in L858R, L858R-L747S, and L858R-T790M cells.</p>\n <p>(B) Modulation of signaling following gefitinib treatment in Ba/F3 cells expressing EGFR mutants. Time course of gefitinib treatment in L858R (LR), L858R-L747S #4 (LR-LS), or L858R-T790M (LR-TM) cells. Cells were treated with 0.2 μM gefitinib for indicated times in the absence of IL3 and in the presence of EGF 20 ng/ml. Note that increase in BIM expression is delayed in LR-LS cells or minimal in LR-TM cells.</p>\n <p>(C) Flow cytometric analysis of the inner mitochondrial membrane potential (ΔΨ<sub>m</sub>) breakdown. Cells were treated in the presence or absence of 0.2 μM gefitinib for 12 or 24 h, and stained with DiOC6(3).</p>\n <p>(D) Activation of caspase-3 and cleavage of PARP are attenuated in L858R-L747S #4 (LR-LS) and L858R-T790M (LR-TM) cells. Cell extracts described in (B) were analyzed by Western blotting.</p></div>", "links"=>[], "tags"=>["resistant", "mutations", "l747s", "t790m", "gefitinib-induced", "apoptosis", "inhibit", "bim"], "article_id"=>613888, "categories"=>["Cancer", "Medicine", "Cell Biology", "Pharmacology"], "users"=>["Daniel B Costa", "Balázs Halmos", "Amit Kumar", "Susan T Schumer", "Mark S Huberman", "Titus J Boggon", "Daniel G Tenen", "Susumu Kobayashi"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.0040315.g006", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_Secondary_Resistant_Mutations_L747S_and_T790M_Affect_Gefitinib_Induced_Apoptosis_and_Inhibit_BIM_Up_Regulation_/613888", "title"=>"The Secondary Resistant Mutations L747S and T790M Affect Gefitinib-Induced Apoptosis and Inhibit BIM Up-Regulation", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2007-10-30 01:04:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/464442", "https://ndownloader.figshare.com/files/464452", "https://ndownloader.figshare.com/files/464461", "https://ndownloader.figshare.com/files/464481"], "description"=>"<div><h3>Background</h3><p>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.</p> <h3>Methods and Findings</h3><p>To study TKI-induced cell death and mechanisms of resistance, we used lung cancer cell lines (with or without <em>EGFR</em> mutations), Ba/F3 cells stably transfected with <em>EGFR</em> 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 <em>EGFR</em>-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.</p> <h3>Conclusions</h3><p>Our results provide evidence that BIM is involved in TKI-induced apoptosis in sensitive <em>EGFR</em>-mutant cells and that both attenuation of the up-regulation of BIM and resistance to gefitinib-induced 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.</p> </div>", "links"=>[], "tags"=>["bim", "mediates", "egfr", "tyrosine", "kinase", "inhibitor-induced", "apoptosis", "cancers", "oncogenic", "mutations"], "article_id"=>151537, "categories"=>["Cancer", "Medicine", "Cell Biology", "Pharmacology"], "users"=>["Daniel B Costa", "Balázs Halmos", "Amit Kumar", "Susan T Schumer", "Mark S Huberman", "Titus J Boggon", "Daniel G Tenen", "Susumu Kobayashi"], "doi"=>["https://dx.doi.org/10.1371/journal.pmed.0040315.sg001", "https://dx.doi.org/10.1371/journal.pmed.0040315.sg002", "https://dx.doi.org/10.1371/journal.pmed.0040315.sg003", "https://dx.doi.org/10.1371/journal.pmed.0040315.st001"], "stats"=>{"downloads"=>22, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/BIM_Mediates_EGFR_Tyrosine_Kinase_Inhibitor_Induced_Apoptosis_in_Lung_Cancers_with_Oncogenic_EGFR_Mutations_/151537", "title"=>"BIM Mediates EGFR Tyrosine Kinase Inhibitor-Induced Apoptosis in Lung Cancers with Oncogenic EGFR Mutations", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2007-10-30 00:25:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/943205"], "description"=>"<div><p>(A) HCC827 cells (left) or H1975 cells (right) were transfected with <i>BIM</i> siRNA oligonucleotides or control oligonucleotides for 24 h prior to 0.5 μM gefitinib or 1 μM CL387,785 treatment, respectively. The cells were then treated for 24 and 48 h and lysates were collected and proteins were analyzed by immunoblotting.</p>\n <p>(B) Annexin V apoptosis assay. The cells were treated as above and analyzed after 48 h. The percentage of surviving cells—both Annexin V<sup>−</sup> and propidium iodide<sup>−</sup> cells—was compared with 0.1% DMSO control. The data are reported as mean ± standard deviation (SD) (<i>n</i> ≥ 3).</p></div>", "links"=>[], "tags"=>["leads", "attenuation"], "article_id"=>613603, "categories"=>["Cancer", "Medicine", "Cell Biology", "Pharmacology"], "users"=>["Daniel B Costa", "Balázs Halmos", "Amit Kumar", "Susan T Schumer", "Mark S Huberman", "Titus J Boggon", "Daniel G Tenen", "Susumu Kobayashi"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.0040315.g004", "stats"=>{"downloads"=>2, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Knockdown_of_BIM_Expression_Leads_to_Attenuation_of_Apoptosis_/613603", "title"=>"Knockdown of <i>BIM</i> Expression Leads to Attenuation of Apoptosis", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2007-10-30 01:00:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/943100"], "description"=>"<div><p>The increase in BIM expression and apoptosis are inhibited by the secondary resistant mutation, T790M.</p>\n <p>(A) Modulation of signaling following gefitinib treatment in HCC827 cells expressing EGFR mutants. Time course of gefitinib treatment in HCC827 cells expressing pcDNA3.1 empty vector (HCC/Emp), EGFR-DelL747-S752 (HCC/Del), or EGFR-DelL747-S752+T790M (HCC/Del-TM). Cells were treated with 3 μM gefitinib or CL-387,785 for indicated times, lysates collected, and proteins analyzed by immunoblotting.</p>\n <p>(B) Modulation of signaling following either gefitinib or CL387,785 treatment in H1975 cells. The cells were treated with 1 μM gefitinib or CL-387,785 for the indicated times and extracts were analyzed by Western blotting.</p></div>", "links"=>[], "tags"=>["bim", "up-regulation", "resistant", "t790m"], "article_id"=>613497, "categories"=>["Cancer", "Medicine", "Cell Biology", "Pharmacology"], "users"=>["Daniel B Costa", "Balázs Halmos", "Amit Kumar", "Susan T Schumer", "Mark S Huberman", "Titus J Boggon", "Daniel G Tenen", "Susumu Kobayashi"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.0040315.g003", "stats"=>{"downloads"=>1, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibition_of_BIM_Up_Regulation_by_the_Resistant_T790M_Mutation_/613497", "title"=>"Inhibition of BIM Up-Regulation by the Resistant T790M Mutation", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2007-10-30 00:58:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/942973"], "description"=>"<p>Cells were treated with 1 μM gefitinib for the times (in hours) indicated, and lysates were collected and proteins analyzed by immunoblotting. The three isoforms of BIM, BIM<sub>EL</sub>, BIM<sub>L</sub>, and BIM<sub>S</sub> are shown. Hypophosphorylated BIM migrates faster than the other species [<a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0040315#pmed-0040315-b023\" target=\"_blank\">23</a>].</p>", "links"=>[], "tags"=>["dephosphorylation", "bim", "gefitinib-sensitive", "cells", "wild-type"], "article_id"=>613369, "categories"=>["Cancer", "Medicine", "Cell Biology", "Pharmacology"], "users"=>["Daniel B Costa", "Balázs Halmos", "Amit Kumar", "Susan T Schumer", "Mark S Huberman", "Titus J Boggon", "Daniel G Tenen", "Susumu Kobayashi"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.0040315.g002", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gefitinib_Induces_Expression_and_Dephosphorylation_of_BIM_in_Gefitinib_Sensitive_EGFR_Mutant_Cells_but_Not_in_Cells_with_Wild_Type_EGFR_/613369", "title"=>"Gefitinib Induces Expression and Dephosphorylation of BIM in Gefitinib-Sensitive <i>EGFR</i>-Mutant Cells, but Not in Cells with Wild-Type <i>EGFR</i>", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2007-10-30 00:56:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/943339"], "description"=>"<div><p>(A) Sequencing chromatograms with the <i>EGFR</i> L747S exon 19 and L858R exon 21 by RT-PCR.</p>\n <p>(B) Amino acid alignments of the tyrosine kinase domain in EGFR, ErbB2, and ABL1.</p>\n <p>(C) Active conformation crystal structure of the kinase domain of EGFR in complex with erlotinib [<a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0040315#pmed-0040315-b034\" target=\"_blank\">34</a>]. The graphic shows the spatial locations of residues L747 and L858 as red spheres. The activation loop is orange, helix αC yellow, the glycine-rich P-loop green, and the inhibitor erlotinib yellow. The figure was made using the program PYMOL (<a href=\"http://pymol.sourceforge.net/\" target=\"_blank\">http://pymol.sourceforge.net/</a>). (D) Top: Dose-dependent growth inhibition of Ba/F3 cells expressing EGFR L858R (LR), L858R-T790M (LR-TM), or L858R-L747S (LR-LS) detected by the MTS assay. Error bars indicate standard deviation (<i>n</i> = 4). Four LR-LS clones (#1–4) were obtained from G418 selection. Bottom: Expression of EGFR in Ba/F3 cells expressing L858R, L858R-L747S #1–4, or L858R-T790M.</p>\n <p>(E) Gefitinib release assay. Ba/F3 cells expressing L858R (LR), L858R-L747S #4 (LR-LS), or L858R-T790M (LR-TM) were plated in 24-well plates at a density of 1 × 10<sup>5</sup>/well and treated with 0.1% DMSO (control) or gefitinib for 24 h. Then the cells were washed three times with RPMI and cultured in medium containing 20 ng/ml EGF. The cells were stained with Trypan blue and counted daily. The data are reported as mean ± SD (<i>n</i> = 3).</p></div>", "links"=>[], "tags"=>["resistant"], "article_id"=>613738, "categories"=>["Cancer", "Medicine", "Cell Biology", "Pharmacology"], "users"=>["Daniel B Costa", "Balázs Halmos", "Amit Kumar", "Susan T Schumer", "Mark S Huberman", "Titus J Boggon", "Daniel G Tenen", "Susumu Kobayashi"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.0040315.g005", "stats"=>{"downloads"=>3, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Identification_of_a_Novel_Secondary_Resistant_EGFR_Mutation_L747S_/613738", "title"=>"Identification of a Novel Secondary Resistant <i>EGFR</i> Mutation, L747S", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2007-10-30 01:02:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/942754"], "description"=>"<div><p>Effect of gefitinib on NSCLC cells. A549, H460, H1650, HCC827, H3255, or PC-9 cells were grown in the presence of 0.1% DMSO (control) or 1 μM gefitinib for 48 h. Apoptosis was assessed using propidium iodide and Annexin-V staining.</p>\n <p>(A) Representative flow cytometry data. The numbers represent percentage of cells in the appropriate quadrant. Left lower quadrant, viable cells; right lower quadrant, early apoptotic cells; right upper quadrant, late apoptotic cells.</p>\n <p>(B) Quantification of apoptosis. The y-axis plots the sum of early and late apoptotic cells as mean ± standard error of the mean (<i>n</i> ≥ 3).</p></div>", "links"=>[], "tags"=>["bim", "correlates", "gefitinib-induced", "apoptosis", "nsclc"], "article_id"=>613148, "categories"=>["Cancer", "Medicine", "Cell Biology", "Pharmacology"], "users"=>["Daniel B Costa", "Balázs Halmos", "Amit Kumar", "Susan T Schumer", "Mark S Huberman", "Titus J Boggon", "Daniel G Tenen", "Susumu Kobayashi"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.0040315.g001", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Up_Regulation_of_BIM_Correlates_with_Gefitinib_Induced_Apoptosis_in_NSCLC_Cell_Lines_/613148", "title"=>"Up-Regulation of BIM Correlates with Gefitinib-Induced Apoptosis in NSCLC Cell Lines", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2007-10-30 00:52:28"}

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Relative Metric

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