Gefitinib-Induced Killing of NSCLC Cell Lines Expressing Mutant EGFR Requires BIM and Can Be Enhanced by BH3 Mimetics
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{"title"=>"Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics", "type"=>"journal", "authors"=>[{"first_name"=>"Mark S.", "last_name"=>"Cragg", "scopus_author_id"=>"6701881225"}, {"first_name"=>"Junya", "last_name"=>"Kuroda", "scopus_author_id"=>"57023397100"}, {"first_name"=>"Hamsa", "last_name"=>"Puthalakath", "scopus_author_id"=>"6603351284"}, {"first_name"=>"David C.S.", "last_name"=>"Huang", "scopus_author_id"=>"24467956400"}, {"first_name"=>"Andreas", "last_name"=>"Strasser", "scopus_author_id"=>"7102640217"}], "year"=>2007, "source"=>"PLoS Medicine", "identifiers"=>{"scopus"=>"2-s2.0-35648953299", "pmid"=>"17973573", "sgr"=>"35648953299", "doi"=>"10.1371/journal.pmed.0040316", "isbn"=>"1549-1676 (Electronic)", "issn"=>"15491277", "pui"=>"350035457"}, "id"=>"ff00a30c-05f9-314e-a2cf-740d7c6a387e", "abstract"=>"BACKGROUND The epidermal growth factor receptor (EGFR) plays a critical role in the control of cellular proliferation, differentiation, and survival. Abnormalities in EGF-EGFR signaling, such as mutations that render the EGFR hyperactive or cause overexpression of the wild-type receptor, have been found in a broad range of cancers, including carcinomas of the lung, breast, and colon. EGFR inhibitors such as gefitinib have proven successful in the treatment of certain cancers, particularly non-small cell lung cancers (NSCLCs) harboring activating mutations within the EGFR gene, but the molecular mechanisms leading to tumor regression remain unknown. Therefore, we wished to delineate these mechanisms. METHODS AND FINDINGS We performed biochemical and genetic studies to investigate the mechanisms by which inhibitors of EGFR tyrosine kinase activity, such as gefitinib, inhibit the growth of human NSCLCs. We found that gefitinib triggered intrinsic (also called \"mitochondrial\") apoptosis signaling, involving the activation of BAX and mitochondrial release of cytochrome c, ultimately unleashing the caspase cascade. Gefitinib caused a rapid increase in the level of the proapoptotic BH3-only protein BIM (also called BCL2-like 11) through both transcriptional and post-translational mechanisms. Experiments with pharmacological inhibitors indicated that blockade of MEK-ERK1/2 (mitogen-activated protein kinase kinase-extracellular signal-regulated protein kinase 1/2) signaling, but not blockade of PI3K (phosphatidylinositol 3-kinase), JNK (c-Jun N-terminal kinase or mitogen-activated protein kinase 8), or AKT (protein kinase B), was critical for BIM activation. Using RNA interference, we demonstrated that BIM is essential for gefitinib-induced killing of NSCLC cells. Moreover, we found that gefitinib-induced apoptosis is enhanced by addition of the BH3 mimetic ABT-737. CONCLUSIONS Inhibitors of the EGFR tyrosine kinase have proven useful in the therapy of certain cancers, in particular NSCLCs possessing activating mutations in the EGFR kinase domain, but the mechanisms of tumor cell killing are still unclear. In this paper, we demonstrate that activation of the proapoptotic BH3-only protein BIM is essential for tumor cell killing and that shutdown of the EGFR-MEK-ERK signaling cascade is critical for BIM activation. Moreover, we demonstrate that addition of a BH3 mimetic significantly enhances killing of NSCLC cells by the EGFR tyrosine kinase inhibitor gefitinib. It appears likely that this approach represents a paradigm shared by many, and perhaps all, oncogenic tyrosine kinases and suggests a powerful new strategy for cancer therapy.", "link"=>"http://www.mendeley.com/research/gefitinibinduced-killing-nsclc-cell-lines-expressing-mutant-egfr-requires-bim-enhanced-bh3-mimetics", "reader_count"=>70, "reader_count_by_academic_status"=>{"Unspecified"=>5, "Professor > Associate Professor"=>3, "Librarian"=>1, "Researcher"=>20, "Student > Doctoral Student"=>5, "Student > Ph. D. Student"=>17, "Student > Postgraduate"=>3, "Student > Master"=>5, "Other"=>4, "Student > Bachelor"=>5, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>5, "Professor > Associate Professor"=>3, "Librarian"=>1, "Researcher"=>20, "Student > Doctoral Student"=>5, "Student > Ph. D. Student"=>17, "Student > Postgraduate"=>3, "Student > Master"=>5, "Other"=>4, "Student > Bachelor"=>5, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>6, "Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>3, "Agricultural and Biological Sciences"=>40, "Medicine and Dentistry"=>11, "Design"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>4, "Chemistry"=>2, "Computer Science"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Design"=>{"Design"=>1}, "Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>11}, "Chemistry"=>{"Chemistry"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>40}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>6}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>4}}, "reader_count_by_country"=>{"Sweden"=>1, "United States"=>1, "United Kingdom"=>3}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/942818"], "description"=>"<div><p>(A and B) H3255 cells were treated with UO126 (UO, 20 μM), PD98059 (PD, 20 μM), LY294002 (LY, 25 μM), Sp6 (20 μM), or gefitinib (Gef, 1 μM) for 1 h (A) or 16 h (B) and then harvested, lysed, and assessed by Western blotting. Blots were probed for phosphorylated AKT (pAKT), total AKT (T AKT), phosphorylated ERK (pERK), total ERK (T ERK) and BIM.</p>\n <p>(C) H1650 and HCC827 cells were treated for 24 h with either UO126 (20 μM) or gefitinib (1 μM) and then harvested, lysed, and assessed by Western blotting for the levels of BIM, phosphorylated ERK (pERK), and total ERK (T ERK).</p>\n <p>(D) H3255 cells were treated for 16 h with gefitinib (Gef, 1 μM), LY294002 (LY, 25 μM), Wortmannin (Wm, 1 μM), AKT inhibitor (AI, 20 μM), or rapamycin (Ra, 100 ng/ml) and then harvested, lysed, and assessed by Western blotting as in (A).</p>\n <p>(E) H3255 cells were treated for 16 h with various combinations of cetuximab (C, 10 μg/ml), UO126 (20 μM), erlotinib (E, 1 μM), or gefitinib (Gef, 1 μM) and then harvested, lysed, and assessed by Western blotting as in (A).</p>\n <p>(F) H3255 cells were treated for 48 h with various combinations of cetuximab (C, 10 μg/ml), UO126 (20 μM), or gefitinib (Gef, 1 μM) and then cell death assessed as previously. Data represent means ± SEM of at least three experiments.</p></div>", "links"=>[], "tags"=>["shutdown", "akt", "pathways", "bim", "dephosphorylation"], "article_id"=>613217, "categories"=>["Cancer", "Biochemistry", "Cell Biology", "Genetics"], "users"=>["Mark S Cragg", "Junya Kuroda", "Hamsa Puthalakath", "David C. S Huang", "Andreas Strasser"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.0040316.g004", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Role_of_Shutdown_of_the_MEK_JNK_PI3K_and_AKT_Signaling_Pathways_in_BIM_Dephosphorylation_and_Accumulation_/613217", "title"=>"Role of Shutdown of the MEK, JNK, PI3K, and AKT Signaling Pathways in BIM Dephosphorylation and Accumulation", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2007-10-30 00:53:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/464361", "https://ndownloader.figshare.com/files/464369", "https://ndownloader.figshare.com/files/464382", "https://ndownloader.figshare.com/files/464394", "https://ndownloader.figshare.com/files/464407", "https://ndownloader.figshare.com/files/464416"], "description"=>"<div><h3>Background</h3><p>The epidermal growth factor receptor (EGFR) plays a critical role in the control of cellular proliferation, differentiation, and survival. Abnormalities in EGF-EGFR signaling, such as mutations that render the EGFR hyperactive or cause overexpression of the wild-type receptor, have been found in a broad range of cancers, including carcinomas of the lung, breast, and colon. EGFR inhibitors such as gefitinib have proven successful in the treatment of certain cancers, particularly non-small cell lung cancers (NSCLCs) harboring activating mutations within the <em>EGFR</em> gene, but the molecular mechanisms leading to tumor regression remain unknown. Therefore, we wished to delineate these mechanisms.</p> <h3>Methods and Findings</h3><p>We performed biochemical and genetic studies to investigate the mechanisms by which inhibitors of EGFR tyrosine kinase activity, such as gefitinib, inhibit the growth of human NSCLCs. We found that gefitinib triggered intrinsic (also called “mitochondrial”) apoptosis signaling, involving the activation of BAX and mitochondrial release of cytochrome <em>c</em>, ultimately unleashing the caspase cascade. Gefitinib caused a rapid increase in the level of the proapoptotic BH3-only protein BIM (also called BCL2-like 11) through both transcriptional and post-translational mechanisms. Experiments with pharmacological inhibitors indicated that blockade of MEK–ERK1/2 (mitogen-activated protein kinase kinase–extracellular signal-regulated protein kinase 1/2) signaling, but not blockade of PI3K (phosphatidylinositol 3-kinase), JNK (c-Jun N-terminal kinase or mitogen-activated protein kinase 8), or AKT (protein kinase B), was critical for BIM activation. Using RNA interference, we demonstrated that BIM is essential for gefitinib-induced killing of NSCLC cells. Moreover, we found that gefitinib-induced apoptosis is enhanced by addition of the BH3 mimetic ABT-737.</p> <h3>Conclusions</h3><p>Inhibitors of the EGFR tyrosine kinase have proven useful in the therapy of certain cancers, in particular NSCLCs possessing activating mutations in the EGFR kinase domain, but the mechanisms of tumor cell killing are still unclear. In this paper, we demonstrate that activation of the proapoptotic BH3-only protein BIM is essential for tumor cell killing and that shutdown of the EGFR–MEK–ERK signaling cascade is critical for BIM activation. Moreover, we demonstrate that addition of a BH3 mimetic significantly enhances killing of NSCLC cells by the EGFR tyrosine kinase inhibitor gefitinib. It appears likely that this approach represents a paradigm shared by many, and perhaps all, oncogenic tyrosine kinases and suggests a powerful new strategy for cancer therapy.</p> </div>", "links"=>[], "tags"=>["gefitinib-induced", "nsclc", "lines", "expressing", "mutant", "requires", "bim", "enhanced", "bh3", "mimetics"], "article_id"=>151522, "categories"=>["Cancer", "Biochemistry", "Cell Biology", "Genetics"], "users"=>["Mark S Cragg", "Junya Kuroda", "Hamsa Puthalakath", "David C. S Huang", "Andreas Strasser"], "doi"=>["https://dx.doi.org/10.1371/journal.pmed.0040316.sg001", "https://dx.doi.org/10.1371/journal.pmed.0040316.sg002", "https://dx.doi.org/10.1371/journal.pmed.0040316.sg003", "https://dx.doi.org/10.1371/journal.pmed.0040316.sg004", "https://dx.doi.org/10.1371/journal.pmed.0040316.sg005", "https://dx.doi.org/10.1371/journal.pmed.0040316.sg006"], "stats"=>{"downloads"=>27, "page_views"=>205, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Gefitinib_Induced_Killing_of_NSCLC_Cell_Lines_Expressing_Mutant_EGFR_Requires_BIM_and_Can_Be_Enhanced_by_BH3_Mimetics/151522", "title"=>"Gefitinib-Induced Killing of NSCLC Cell Lines Expressing Mutant <em>EGFR</em> Requires BIM and Can Be Enhanced by BH3 Mimetics", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2007-10-30 00:25:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/942592"], "description"=>"<div><p>(A) In the blot on the left, H1650 cells were left untreated (NT) or treated with 1 μM gefitinib (G) for 24, 48, or 72 h and the cells harvested, lysed, and assessed by Western blotting for the expression of BIM. HCC827 or H3255 cells (center and right, respectively) were treated for 16 h with a range of concentrations of gefitinib (10–0.08 μM) and the expression of BIM analyzed as above. Actin is shown as a loading control.</p>\n <p>(B) H1650 or H3255 cells were treated as in (A) and then BH3-only proteins, prosurvival BCL-2 family members, or β-actin (loading control) assessed by Western blotting.</p>\n <p>(C) H3255 cells were left untreated (NT) or treated for 16 h with 1 μM gefitinib (Gef) and the cells harvested and lysed. Portions of the samples were then treated with λ-phosphatase (+) or left untreated (−) and then assessed by Western blotting for BIM (labeled Bim<sub>EL</sub> and Bim<sub>L</sub>).</p>\n <p>(D) H3255 cells were left untreated or treated for 16 h with 1 μM gefitinib and the cells harvested and lysed. BIM (labeled Bim<sub>EL</sub> and Bim<sub>L</sub>) was isolated by immunoaffinity chromatography and subjected to two-dimensional gel SDS-PAGE followed by Western blotting for BIM.</p></div>", "links"=>[], "tags"=>["dephosphorylation", "bim", "gefitinib", "nsclc", "cells", "expressing", "mutant"], "article_id"=>612995, "categories"=>["Cancer", "Biochemistry", "Cell Biology", "Genetics"], "users"=>["Mark S Cragg", "Junya Kuroda", "Hamsa Puthalakath", "David C. S Huang", "Andreas Strasser"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.0040316.g002", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Induction_and_Dephosphorylation_of_BIM_after_Gefitinib_Treatment_in_NSCLC_Cells_Expressing_Mutant_EGFR_/612995", "title"=>"Induction and Dephosphorylation of BIM after Gefitinib Treatment in NSCLC Cells Expressing Mutant EGFR", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2007-10-30 00:49:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/942917"], "description"=>"<p>H358, H1650, H1975, and H3255 cells were treated with gefitinib (H358, H1975, and H1650, 10 μM gefitinib; H3255, 1 μM gefitinib) in the presence or absence of ABT-737 (1 μM) for 32 h (H3255 cells) or 48 h (H358, H1650, H1975 cells). Cells were then harvested and survival measured as in <a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0040316#pmed-0040316-g001\" target=\"_blank\">Figure 1</a>B. Data represent means ± SEM of three experiments indicating percentage of cell death compared to untreated cells.</p>", "links"=>[], "tags"=>["gefitinib", "abt-737", "nsclc", "cells", "expressing", "activating", "mutations"], "article_id"=>613313, "categories"=>["Cancer", "Biochemistry", "Cell Biology", "Genetics"], "users"=>["Mark S Cragg", "Junya Kuroda", "Hamsa Puthalakath", "David C. S Huang", "Andreas Strasser"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.0040316.g005", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Synergy_between_Gefitinib_and_ABT_737_in_Killing_of_NSCLC_Cells_Expressing_Activating_Mutations_of_EGFR_/613313", "title"=>"Synergy between Gefitinib and ABT-737 in Killing of NSCLC Cells Expressing Activating Mutations of <i>EGFR</i>", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2007-10-30 00:55:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/942696"], "description"=>"<div><p>(A) Western blot analysis documents the level of <i>BIM</i> expression in parental and <i>BIM</i> RNAi knockdown subclones of H3255 cells. Probing with an antibody to total ERK (T ERK) was used as a loading control.</p>\n <p>(B and C) Parental and <i>BIM</i> RNAi knockdown subclone #21 of H3255 cells were left untreated (NT) or treated for 18 h with gefitinib (1–0.04 μM) prior to cell lysis and Western blotting (B) or assessment of cell death (C). Blots (B) were probed with antibodies specific to phosphorylated EGFR (pEGFR), phosphorylated ERK (pERK), BIM or β-actin (loading control). Cell viability (C) was determined by staining with Annexin V-FITC plus PI, followed by flow cytometric analysis.</p>\n <p>(D) Parental and <i>BIM</i> RNAi knockdown subclones (#21, #27, and #42) of H3255 cells were treated for 24 h with DMSO (vehicle control; NT) or 1 μM gefitinib and cell death assessed as above. Data represent means ± SEM of three experiments.</p></div>", "links"=>[], "tags"=>["knockdown", "rnai", "protects", "h3255", "cells", "gefitinib-induced"], "article_id"=>613100, "categories"=>["Cancer", "Biochemistry", "Cell Biology", "Genetics"], "users"=>["Mark S Cragg", "Junya Kuroda", "Hamsa Puthalakath", "David C. S Huang", "Andreas Strasser"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.0040316.g003", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_BIM_Knockdown_by_RNAi_Protects_H3255_Cells_against_Gefitinib_Induced_Killing_/613100", "title"=>"<i>BIM</i> Knockdown by RNAi Protects H3255 Cells against Gefitinib-Induced Killing", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2007-10-30 00:51:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/942496"], "description"=>"<p>NSCLC cells expressing WT (H358) or mutant (HCC827, H1975, H1650, H3255) <i>EGFR</i> were treated with varying concentrations of gefitinib for 24 h (A) or 72 h (B). Cells were then either assessed for the phosphorylation status of ERK (A) or cell death (B). Western blotting (A) was performed to determine the phosphorylation status of ERK1/2 before and after treatment with gefitinib. An actin loading control is also shown. Cell death was assessed by Annexin V-FITC plus PI staining (B). Results represent mean ± standard error of the mean (SEM) of at least three experiments. NT, no treatment.</p>", "links"=>[], "tags"=>["gefitinib", "nsclc", "cells", "expressing", "wt", "mutant"], "article_id"=>612898, "categories"=>["Cancer", "Biochemistry", "Cell Biology", "Genetics"], "users"=>["Mark S Cragg", "Junya Kuroda", "Hamsa Puthalakath", "David C. S Huang", "Andreas Strasser"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.0040316.g001", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_Gefitinib_on_NSCLC_Cells_Expressing_WT_or_Mutant_EGFR_/612898", "title"=>"Effect of Gefitinib on NSCLC Cells Expressing WT or Mutant <i>EGFR</i>", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2007-10-30 00:48:18"}

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Relative Metric

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