Fibroblast Growth Factor Receptors as Novel Therapeutic Targets in SNF5-Deleted Malignant Rhabdoid Tumors
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{"title"=>"Fibroblast Growth Factor Receptors as Novel Therapeutic Targets in SNF5-Deleted Malignant Rhabdoid Tumors", "type"=>"journal", "authors"=>[{"first_name"=>"Simon", "last_name"=>"Wöhrle"}, {"first_name"=>"Andreas", "last_name"=>"Weiss"}, {"first_name"=>"Moriko", "last_name"=>"Ito"}, {"first_name"=>"Audrey", "last_name"=>"Kauffmann"}, {"first_name"=>"Masato", "last_name"=>"Murakami"}, {"first_name"=>"Zainab", "last_name"=>"Jagani"}, {"first_name"=>"Anne", "last_name"=>"Thuery"}, {"first_name"=>"Beatrice", "last_name"=>"Bauer-Probst"}, {"first_name"=>"Flavia", "last_name"=>"Reimann"}, {"first_name"=>"Christelle", "last_name"=>"Stamm"}, {"first_name"=>"Astrid", "last_name"=>"Pornon"}, {"first_name"=>"Vincent", "last_name"=>"Romanet"}, {"first_name"=>"Vito", "last_name"=>"Guagnano"}, {"first_name"=>"Thomas", "last_name"=>"Brümmendorf"}, {"first_name"=>"William R.", "last_name"=>"Sellers"}, {"first_name"=>"Francesco", "last_name"=>"Hofmann"}, {"first_name"=>"Charles W. M.", "last_name"=>"Roberts"}, {"first_name"=>"Diana", "last_name"=>"Graus Porta"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"563079815", "sgr"=>"84905288222", "issn"=>"1932-6203", "pmid"=>"24204904", "scopus"=>"2-s2.0-84905288222", "doi"=>"10.1371/journal.pone.0077652"}, "id"=>"0cc310e9-8718-3440-b871-f9eb6d15ff23", "abstract"=>"Malignant rhabdoid tumors (MRTs) are aggressive pediatric cancers arising in brain, kidney and soft tissues, which are characterized by loss of the tumor suppressor SNF5/SMARCB1. MRTs are poorly responsive to chemotherapy and thus a high unmet clinical need exists for novel therapies for MRT patients. SNF5 is a core subunit of the SWI/SNF chromatin remodeling complex which affects gene expression by nucleosome remodeling. Here, we report that loss of SNF5 function correlates with increased expression of fibroblast growth factor receptors (FGFRs) in MRT cell lines and primary tumors and that re-expression of SNF5 in MRT cells causes a marked repression of FGFR expression. Conversely, siRNA-mediated impairment of SWI/SNF function leads to elevated levels of FGFR2 in human fibroblasts. In vivo, treatment with NVP-BGJ398, a selective FGFR inhibitor, blocks progression of a murine MRT model. Hence, we identify FGFR signaling as an aberrantly activated oncogenic pathway in MRTs and propose pharmacological inhibition of FGFRs as a potential novel clinical therapy for MRTs.", "link"=>"http://www.mendeley.com/research/fibroblast-growth-factor-receptors-novel-therapeutic-targets-snf5deleted-malignant-rhabdoid-tumors-2", "reader_count"=>17, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Researcher"=>3, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>5, "Student > Master"=>4, "Student > Bachelor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Researcher"=>3, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>5, "Student > Master"=>4, "Student > Bachelor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>3, "Agricultural and Biological Sciences"=>9, "Medicine and Dentistry"=>4}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>9}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>1}}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/4364665"], "description"=>"<p>(A) <i>In vivo</i> efficacy of NVP-BGJ398 in a primary mouse MRT allograft model. MRT bearing nude mice received vehicle or NVP-BGJ398 at 50 mg/kg body weight for 13 consecutive days and tumor volumes were monitored. Date are given as average with SEM (n = 4) and were compared by unpaired Student’s t test; *p<0.05. (B) Immunohistochemistry (IHC, upper panel) and immunoblot (lower panel) analysis of p-ERK1/2 levels in MRT allograft samples from mice treated with a single dose of vehicle or NVP-BGJ398 (50 mg/kg body weight) for 2 h. β-Tubulin expression was used to monitor equal loading.</p>", "links"=>[], "tags"=>["murine MRT model", "fibroblast growth factor receptors", "SNF 5 function correlates", "MRT cell lines", "MRT cells causes", "Fibroblast Growth Factor Receptors", "FGFR", "tumor", "expression", "SWI", "SNF 5"], "article_id"=>837627, "categories"=>["Medicine", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biological Sciences not elsewhere classified", "Cancer"], "users"=>["Simon Wöhrle", "Andreas Weiss", "Moriko Ito", "Audrey Kauffmann", "Masato Murakami", "Zainab Jagani", "Anne Thuery", "Beatrice Bauer-Probst", "Flavia Reimann", "Christelle Stamm", "Astrid Pornon", "Vincent Romanet", "Vito Guagnano", "Thomas Brümmendorf", "William R. Sellers", "Francesco Hofmann", "Charles W. M. Roberts", "Diana Graus Porta"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0077652.g006"], "stats"=>{"downloads"=>3, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_FGFR_inhibition_with_NVP_BGJ398_impairs_MRT_growth_in_vivo_/837627", "title"=>"FGFR inhibition with NVP-BGJ398 impairs MRT growth <i>in vivo</i>.", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-10-30 20:52:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/4364656"], "description"=>"<p>(A) Schematic overview of the human FGFR2 promoter. Amplicons of primer pairs used for ChIP are shown as red squares and location is indicated relative to the transcriptional start site (TSS, +1). Exons are shown as blue boxes. (B) FGFR2 promoter occupancy by SNF5 in BJ cells. Fold enrichment from chromatin immunoprecititaions (ChIP) with a SNF5-specific antibody compared to an IgG control was analyzed by qPCR using the primer pairs indicated in (A). (C) Fold enrichment of the negative control locus IGX1A and the promoter region of the known SNF5 target gene CDKN1A. Fold enrichment is given as average with SEM (n≥3). Data were compared by unpaired Student’s t test with respect to the fold enrichment of the IGX1A locus; *p<0.05.</p>", "links"=>[], "tags"=>["murine MRT model", "fibroblast growth factor receptors", "SNF 5 function correlates", "MRT cell lines", "MRT cells causes", "Fibroblast Growth Factor Receptors", "FGFR", "tumor", "expression", "SWI", "SNF 5"], "article_id"=>837626, "categories"=>["Medicine", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biological Sciences not elsewhere classified", "Cancer"], "users"=>["Simon Wöhrle", "Andreas Weiss", "Moriko Ito", "Audrey Kauffmann", "Masato Murakami", "Zainab Jagani", "Anne Thuery", "Beatrice Bauer-Probst", "Flavia Reimann", "Christelle Stamm", "Astrid Pornon", "Vincent Romanet", "Vito Guagnano", "Thomas Brümmendorf", "William R. Sellers", "Francesco Hofmann", "Charles W. M. Roberts", "Diana Graus Porta"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0077652.g005"], "stats"=>{"downloads"=>0, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SNF5_is_recruited_to_the_FGFR2_promoter_in_BJ_cells_/837626", "title"=>"SNF5 is recruited to the FGFR2 promoter in BJ cells.", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-10-30 20:52:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/4364632"], "description"=>"<p>(A) Global compound selectivity analysis of MRT lines. Comparison of the three MRT lines A204, G401 and G402 versus other soft tissue cancer lines from the CCLE with regards to sensitivity to a panel of approximately 2000 compounds with defined target specificity. Shown are the top 5 enriched target in MRTs according to Activity Area and Inflection Point scores. FDR, false discovery rate. (B) Sensitivity towards the FGFR inhibitor NVP-BGJ398 among soft tissue cancer lines. A cut-off value of 500 nM was used to determine NVP-BGJ398 sensitivity based on Crossing Point values from high-throughput cell proliferation assays. (C) Immunoblot analysis of p-FRS2 and p-ERK1/2 in MRT lines treated with DMSO or NVP-BGJ398 for 40 min as indicated. Total ERK1/2 and β-Tubulin expression was used to monitor equal loading.</p>", "links"=>[], "tags"=>["murine MRT model", "fibroblast growth factor receptors", "SNF 5 function correlates", "MRT cell lines", "MRT cells causes", "Fibroblast Growth Factor Receptors", "FGFR", "tumor", "expression", "SWI", "SNF 5"], "article_id"=>837620, "categories"=>["Medicine", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biological Sciences not elsewhere classified", "Cancer"], "users"=>["Simon Wöhrle", "Andreas Weiss", "Moriko Ito", "Audrey Kauffmann", "Masato Murakami", "Zainab Jagani", "Anne Thuery", "Beatrice Bauer-Probst", "Flavia Reimann", "Christelle Stamm", "Astrid Pornon", "Vincent Romanet", "Vito Guagnano", "Thomas Brümmendorf", "William R. Sellers", "Francesco Hofmann", "Charles W. M. Roberts", "Diana Graus Porta"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0077652.g001"], "stats"=>{"downloads"=>0, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MRT_cell_lines_are_sensitive_to_pharmacological_FGFR_inhibition_/837620", "title"=>"MRT cell lines are sensitive to pharmacological FGFR inhibition.", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-10-30 20:52:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/4364677"], "description"=>"<p>Scatter plot showing expression of <i>FGFR1</i> (left panel) and <i>FGFR2</i> (right panel) versus <i>SNF5</i> levels among human primary sarcoma samples. MRTs are indicated in red. Dashed line indicates threshold of 10<sup>th</sup> percentile of highest <i>FGFR1</i> or <i>FGFR2</i> expression in sample set.</p>", "links"=>[], "tags"=>["murine MRT model", "fibroblast growth factor receptors", "SNF 5 function correlates", "MRT cell lines", "MRT cells causes", "Fibroblast Growth Factor Receptors", "FGFR", "tumor", "expression", "SWI", "SNF 5"], "article_id"=>837629, "categories"=>["Medicine", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biological Sciences not elsewhere classified", "Cancer"], "users"=>["Simon Wöhrle", "Andreas Weiss", "Moriko Ito", "Audrey Kauffmann", "Masato Murakami", "Zainab Jagani", "Anne Thuery", "Beatrice Bauer-Probst", "Flavia Reimann", "Christelle Stamm", "Astrid Pornon", "Vincent Romanet", "Vito Guagnano", "Thomas Brümmendorf", "William R. Sellers", "Francesco Hofmann", "Charles W. M. Roberts", "Diana Graus Porta"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0077652.g007"], "stats"=>{"downloads"=>1, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_FGFR1_and_FGFR2_expression_in_human_primary_MRTs_/837629", "title"=>"FGFR1 and FGFR2 expression in human primary MRTs.", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-10-30 20:52:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/4364644"], "description"=>"<p>(A) Immunoblot analysis (left panel) of FGFR2 protein expression in G401 cells five days post retroviral transduction of SNF5. β-Tubulin expression was used to monitor equal loading. <i>FGFR2</i> mRNA levels (right panel) were determined by qRT-PCR. Expression is shown as relative levels to control infected cells. Data are given as average with SEM (n = 3). <i>FGFR2</i> mRNA expression values were normalized to <i>GAPDH</i> mRNA copies. Data were compared by unpaired Student’s t test; *p<0.05. (B) Analysis of FGFR1 protein and mRNA expression in G402 cells upon re-expression of SNF5 as described in (A).</p>", "links"=>[], "tags"=>["murine MRT model", "fibroblast growth factor receptors", "SNF 5 function correlates", "MRT cell lines", "MRT cells causes", "Fibroblast Growth Factor Receptors", "FGFR", "tumor", "expression", "SWI", "SNF 5"], "article_id"=>837623, "categories"=>["Medicine", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biological Sciences not elsewhere classified", "Cancer"], "users"=>["Simon Wöhrle", "Andreas Weiss", "Moriko Ito", "Audrey Kauffmann", "Masato Murakami", "Zainab Jagani", "Anne Thuery", "Beatrice Bauer-Probst", "Flavia Reimann", "Christelle Stamm", "Astrid Pornon", "Vincent Romanet", "Vito Guagnano", "Thomas Brümmendorf", "William R. Sellers", "Francesco Hofmann", "Charles W. M. Roberts", "Diana Graus Porta"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0077652.g003"], "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Re_expression_of_SNF5_in_MRT_lines_abrogates_FGFR_expression_/837623", "title"=>"Re-expression of SNF5 in MRT lines abrogates FGFR expression.", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-10-30 20:52:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/4364650"], "description"=>"<p>(A) Effect of siRNA-mediated knockdown of SNF5 on FGFR2 expression in BJ cells. <i>SNF5</i> and <i>FGFR2</i> expression levels were analyzed by qRT-PCR at 72 h post siRNA transfection. Expression is shown as relative levels to cells transfected with non-targeting control siRNA and is given as average with SEM (n≥3). <i>E</i>xpression values were normalized to <i>GAPDH</i> mRNA copies. (B) Immunoblot analysis of FGFR2 expression upon knockdown of SNF5 in BJ cells as described in (A). β-Tubulin expression was used to monitor equal loading. (C) Effect of siRNA-mediated knockdown of BRG1 on FGFR2 expression in BJ cells as described in (A).</p>", "links"=>[], "tags"=>["murine MRT model", "fibroblast growth factor receptors", "SNF 5 function correlates", "MRT cell lines", "MRT cells causes", "Fibroblast Growth Factor Receptors", "FGFR", "tumor", "expression", "SWI", "SNF 5"], "article_id"=>837624, "categories"=>["Medicine", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biological Sciences not elsewhere classified", "Cancer"], "users"=>["Simon Wöhrle", "Andreas Weiss", "Moriko Ito", "Audrey Kauffmann", "Masato Murakami", "Zainab Jagani", "Anne Thuery", "Beatrice Bauer-Probst", "Flavia Reimann", "Christelle Stamm", "Astrid Pornon", "Vincent Romanet", "Vito Guagnano", "Thomas Brümmendorf", "William R. Sellers", "Francesco Hofmann", "Charles W. M. Roberts", "Diana Graus Porta"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0077652.g004"], "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SNF5_loss_of_function_induces_FGFR2_expression_in_human_fibroblasts_/837624", "title"=>"SNF5 loss of function induces FGFR2 expression in human fibroblasts.", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-10-30 20:52:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/4364638"], "description"=>"<p>(A) Scatter plot showing expression and copy number levels for <i>FGFR1</i> (left panel) and <i>FGFR2</i> (right panel) within the CCLE. MRT lines A204, G401 and G402 are indicated in red. (B) Quantitative RT-PCR (qRT-PCR) analysis of <i>FGFR1</i> and <i>FGFR2</i> mRNA expression in MRT cell lines and soft tissue cancer lines SKLMS1 and SKUT1. Expression values are given as average with standard errors of the mean (SEM) (n≥3) with respect to <i>GAPDH</i> mRNA levels (arbitrarily set as 100). (C) qRT-PCR and immunoblot analysis of SNF5-deficiency in MRT lines. SKLMS1 and SKUT1 cells were used as positive controls for SNF5 expression. <i>SNF5</i> mRNA expression is given as average with SEM (n≥3) with respect to <i>GAPDH</i> mRNA levels (arbitrarily set as 100). β-Tubulin expression was used to monitor equal loading.</p>", "links"=>[], "tags"=>["murine MRT model", "fibroblast growth factor receptors", "SNF 5 function correlates", "MRT cell lines", "MRT cells causes", "Fibroblast Growth Factor Receptors", "FGFR", "tumor", "expression", "SWI", "SNF 5"], "article_id"=>837622, "categories"=>["Medicine", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biological Sciences not elsewhere classified", "Cancer"], "users"=>["Simon Wöhrle", "Andreas Weiss", "Moriko Ito", "Audrey Kauffmann", "Masato Murakami", "Zainab Jagani", "Anne Thuery", "Beatrice Bauer-Probst", "Flavia Reimann", "Christelle Stamm", "Astrid Pornon", "Vincent Romanet", "Vito Guagnano", "Thomas Brümmendorf", "William R. Sellers", "Francesco Hofmann", "Charles W. M. Roberts", "Diana Graus Porta"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0077652.g002"], "stats"=>{"downloads"=>1, "page_views"=>42, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_FGFR_expression_levels_of_the_MRT_cell_lines_A204_G401_and_G402_/837622", "title"=>"FGFR expression levels of the MRT cell lines A204, G401 and G402.", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-10-30 20:52:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/4364575", "https://ndownloader.figshare.com/files/4364590", "https://ndownloader.figshare.com/files/4364599", "https://ndownloader.figshare.com/files/4364608", "https://ndownloader.figshare.com/files/4364620", "https://ndownloader.figshare.com/files/4364623", "https://ndownloader.figshare.com/files/4364626"], "description"=>"<div><p>Malignant rhabdoid tumors (MRTs) are aggressive pediatric cancers arising in brain, kidney and soft tissues, which are characterized by loss of the tumor suppressor SNF5/SMARCB1. MRTs are poorly responsive to chemotherapy and thus a high unmet clinical need exists for novel therapies for MRT patients. SNF5 is a core subunit of the SWI/SNF chromatin remodeling complex which affects gene expression by nucleosome remodeling. Here, we report that loss of SNF5 function correlates with increased expression of fibroblast growth factor receptors (FGFRs) in MRT cell lines and primary tumors and that re-expression of SNF5 in MRT cells causes a marked repression of FGFR expression. Conversely, siRNA-mediated impairment of SWI/SNF function leads to elevated levels of FGFR2 in human fibroblasts. In vivo, treatment with NVP-BGJ398, a selective FGFR inhibitor, blocks progression of a murine MRT model. Hence, we identify FGFR signaling as an aberrantly activated oncogenic pathway in MRTs and propose pharmacological inhibition of FGFRs as a potential novel clinical therapy for MRTs.</p></div>", "links"=>[], "tags"=>["murine MRT model", "fibroblast growth factor receptors", "SNF 5 function correlates", "MRT cell lines", "MRT cells causes", "Fibroblast Growth Factor Receptors", "FGFR", "tumor", "expression", "SWI", "SNF 5"], "article_id"=>837631, "categories"=>["Medicine", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biological Sciences not elsewhere classified", "Cancer"], "users"=>["Simon Wöhrle", "Andreas Weiss", "Moriko Ito", "Audrey Kauffmann", "Masato Murakami", "Zainab Jagani", "Anne Thuery", "Beatrice Bauer-Probst", "Flavia Reimann", "Christelle Stamm", "Astrid Pornon", "Vincent Romanet", "Vito Guagnano", "Thomas Brümmendorf", "William R. Sellers", "Francesco Hofmann", "Charles W. M. Roberts", "Diana Graus Porta"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0077652.s001", "https://dx.doi.org/10.1371/journal.pone.0077652.s002", "https://dx.doi.org/10.1371/journal.pone.0077652.s003", "https://dx.doi.org/10.1371/journal.pone.0077652.s004", "https://dx.doi.org/10.1371/journal.pone.0077652.s005", "https://dx.doi.org/10.1371/journal.pone.0077652.s006", "https://dx.doi.org/10.1371/journal.pone.0077652.s007"], "stats"=>{"downloads"=>0, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Fibroblast_Growth_Factor_Receptors_as_Novel_Therapeutic_Targets_in_SNF5_Deleted_Malignant_Rhabdoid_Tumors_/837631", "title"=>"Fibroblast Growth Factor Receptors as Novel Therapeutic Targets in SNF5-Deleted Malignant Rhabdoid Tumors", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-10-30 20:52:41"}

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Relative Metric

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