CDK1 Is a Synthetic Lethal Target for KRAS Mutant Tumours
Publication Date
February 16, 2016
Journal
PLOS ONE
Authors
Sara Costa Cabral, Rachel Brough, Asha Konde, Marieke Aarts, et al
Volume
11
Issue
2
Pages
e0149099
DOI
https://dx.plos.org/10.1371/journal.pone.0149099
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0149099
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/26881434
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755568
Europe PMC
http://europepmc.org/abstract/MED/26881434
Web of Science
000371219000045
Scopus
84978676921
Mendeley
http://www.mendeley.com/research/cdk1-synthetic-lethal-target-kras-mutant-tumours
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Mendeley | Further Information

{"title"=>"CDK1 Is a synthetic lethal target for KRAS mutant tumours", "type"=>"journal", "authors"=>[{"first_name"=>"Sara", "last_name"=>"Costa-Cabral", "scopus_author_id"=>"36781874400"}, {"first_name"=>"Rachel", "last_name"=>"Brough", "scopus_author_id"=>"23017789800"}, {"first_name"=>"Asha", "last_name"=>"Konde", "scopus_author_id"=>"56010639600"}, {"first_name"=>"Marieke", "last_name"=>"Aarts", "scopus_author_id"=>"15724702700"}, {"first_name"=>"James", "last_name"=>"Campbel", "scopus_author_id"=>"36993639300"}, {"first_name"=>"Eliana", "last_name"=>"Marinari", "scopus_author_id"=>"57190134492"}, {"first_name"=>"Jenna", "last_name"=>"Riffell", "scopus_author_id"=>"55515593800"}, {"first_name"=>"Alberto", "last_name"=>"Bardelli", "scopus_author_id"=>"7006937523"}, {"first_name"=>"Christopher", "last_name"=>"Torrance", "scopus_author_id"=>"7005412386"}, {"first_name"=>"Christopher J.", "last_name"=>"Lord", "scopus_author_id"=>"7101632397"}, {"first_name"=>"Alan", "last_name"=>"Ashworth", "scopus_author_id"=>"35379025100"}], "year"=>2016, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "sgr"=>"84978676921", "doi"=>"10.1371/journal.pone.0149099", "scopus"=>"2-s2.0-84978676921", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"26881434", "pui"=>"611263006"}, "id"=>"6e840d51-14c3-36f4-bfc5-2eaf4bd65a96", "abstract"=>"Activating KRAS mutations are found in approximately 20% of human cancers but no RAS-directed therapies are currently available. Here we describe a novel, robust, KRAS synthetic lethal interaction with the cyclin dependent kinase, CDK1. This was discovered using parallel siRNA screens in KRAS mutant and wild type colorectal isogenic tumour cells and subsequently validated in a genetically diverse panel of 26 colorectal and pancreatic tumour cell models. This established that the KRAS/CDK1 synthetic lethality applies in tumour cells with either amino acid position 12 (p.G12V, pG12D, p.G12S) or amino acid position 13 (p.G13D) KRAS mutations and can also be replicated in vivo in a xenograft model using a small molecule CDK1 inhibitor. Mechanistically, CDK1 inhibition caused a reduction in the S-phase fraction of KRAS mutant cells, an effect also characterised by modulation of Rb, a master control of the G1/S checkpoint. Taken together, these observations suggest that the KRAS/CDK1 interaction is a robust synthetic lethal effect worthy of further investigation.", "link"=>"http://www.mendeley.com/research/cdk1-synthetic-lethal-target-kras-mutant-tumours", "reader_count"=>37, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>1, "Student > Doctoral Student"=>3, "Researcher"=>8, "Student > Ph. D. Student"=>9, "Student > Postgraduate"=>1, "Student > Master"=>8, "Other"=>3, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>1, "Student > Doctoral Student"=>3, "Researcher"=>8, "Student > Ph. D. Student"=>9, "Student > Postgraduate"=>1, "Student > Master"=>8, "Other"=>3, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>13, "Medicine and Dentistry"=>6, "Agricultural and Biological Sciences"=>8, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>5, "Psychology"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Chemistry"=>{"Chemistry"=>5}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>8}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>13}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Austria"=>1, "United Kingdom"=>2, "France"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/3981445", "https://ndownloader.figshare.com/files/3981724", "https://ndownloader.figshare.com/files/3981712", "https://ndownloader.figshare.com/files/3981673", "https://ndownloader.figshare.com/files/3981658", "https://ndownloader.figshare.com/files/3981649", "https://ndownloader.figshare.com/files/3981625", "https://ndownloader.figshare.com/files/3981604", "https://ndownloader.figshare.com/files/3981583", "https://ndownloader.figshare.com/files/3981562", "https://ndownloader.figshare.com/files/3981532", "https://ndownloader.figshare.com/files/3981508", "https://ndownloader.figshare.com/files/3981481", "https://ndownloader.figshare.com/files/3981457", "https://ndownloader.figshare.com/files/3981763"], "description"=>"<div><p>Activating KRAS mutations are found in approximately 20% of human cancers but no RAS-directed therapies are currently available. Here we describe a novel, robust, KRAS synthetic lethal interaction with the cyclin dependent kinase, CDK1. This was discovered using parallel siRNA screens in KRAS mutant and wild type colorectal isogenic tumour cells and subsequently validated in a genetically diverse panel of 26 colorectal and pancreatic tumour cell models. This established that the KRAS/CDK1 synthetic lethality applies in tumour cells with either amino acid position 12 (p.G12V, pG12D, p.G12S) or amino acid position 13 (p.G13D) KRAS mutations and can also be replicated <i>in vivo</i> in a xenograft model using a small molecule CDK1 inhibitor. Mechanistically, CDK1 inhibition caused a reduction in the S-phase fraction of KRAS mutant cells, an effect also characterised by modulation of Rb, a master control of the G<sub>1</sub>/S checkpoint. Taken together, these observations suggest that the KRAS/CDK1 interaction is a robust synthetic lethal effect worthy of further investigation.</p></div>", "links"=>[], "tags"=>["KRAS Mutant Tumours Activating KRAS mutations", "molecule CDK 1 inhibitor", "type colorectal isogenic tumour cells", "CDK 1", "Synthetic Lethal Target", "master control", "acid position 12", "xenograft model", "CDK 1.", "siRNA screens", "tumour cells", "p.G 12V pG 12D p.G 12S", "CDK 1 inhibition", "acid position 13", "26 colorectal", "pancreatic tumour cell models", "p.G 13D KRAS mutations"], "article_id"=>2343361, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biotechnology", "Chemical Sciences not elsewhere classified", "Biological Sciences not elsewhere classified", "Developmental Biology", "Cancer", "Hematology"], "users"=>["Sara Costa-Cabral", "Rachel Brough", "Asha Konde", "Marieke Aarts", "James Campbell", "Eliana Marinari", "Jenna Riffell", "Alberto Bardelli", "Christopher Torrance", "Christopher J. Lord", "Alan Ashworth"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0149099.s001", "https://dx.doi.org/10.1371/journal.pone.0149099.s014", "https://dx.doi.org/10.1371/journal.pone.0149099.s013", "https://dx.doi.org/10.1371/journal.pone.0149099.s012", "https://dx.doi.org/10.1371/journal.pone.0149099.s011", "https://dx.doi.org/10.1371/journal.pone.0149099.s010", "https://dx.doi.org/10.1371/journal.pone.0149099.s009", "https://dx.doi.org/10.1371/journal.pone.0149099.s008", "https://dx.doi.org/10.1371/journal.pone.0149099.s007", "https://dx.doi.org/10.1371/journal.pone.0149099.s006", "https://dx.doi.org/10.1371/journal.pone.0149099.s005", "https://dx.doi.org/10.1371/journal.pone.0149099.s004", "https://dx.doi.org/10.1371/journal.pone.0149099.s003", "https://dx.doi.org/10.1371/journal.pone.0149099.s002", "https://dx.doi.org/10.1371/journal.pone.0149099.s015"], "stats"=>{"downloads"=>8, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/CDK1_Is_a_Synthetic_Lethal_Target_for_KRAS_Mutant_Tumours/2343361", "title"=>"CDK1 Is a Synthetic Lethal Target for KRAS Mutant Tumours", "pos_in_sequence"=>1, "defined_type"=>4, "published_date"=>"2016-02-16 07:56:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/3981829"], "description"=>"<p>(A) Schematic of KRAS isogenic cell lines generation. <i>KRAS</i> mutations were introduced into the parental cell lines via r-AAV-mediated homologous recombination. A general structure of the targeting construct is represented. The resulting mutant <i>KRAS</i> allele is expressed from its endogenous promoter. The <i>Neo</i> cassette is removed from the genome of the targeted cells by Cre recombinase-mediated excision. AAV, adeno-associated virus; ITR, inverted terminal repeat; Neo, geneticin-resistance gene; P, SV40 promoter; triangles, loxP sites (Figure adapted from [<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149099#pone.0149099.ref027\" target=\"_blank\">27</a>]). (B) RAS activation status of LIM1215 KRAS isogenic cell lines. Western blot showing active RAS (RAF1 GTP-bound) levels for LIM1215 KRAS isogenic cell lines. The RAF1 RAS binding domain (RBD) was used to precipitate GTP-RAS. The RAS activation status was tested for each clone with mutated KRAS. Precipitated RAS-GTP was detected by western blot using anti-RAS antibody. As a positive control, HeLa cells (RAS wild-type) were stimulated with epidermal growth factor (EGF) to activate the RAS pathway. HeLa and MCF7 cells (unstimulated) were used as negative controls. Total lysates were also immunoblotted with anti-β-Actin antibody as loading control. (C) and (D) KRAS dependence in the LIM1215 KRAS isogenic cell line models, obtained from the HT siRNA screen described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149099#pone.0149099.g002\" target=\"_blank\">Fig 2</a>. Bar graph of <i>KRAS</i> siRNA Z-score values across the LIM1215 <i>KRAS</i> WT and mutant isogenic cell lines, C and D respectively. KRAS dependence was greater in the cell lines carrying KRAS mutations than in WT cells. Error bars represent SEM from three independent experiments. (E) Western blot of KRAS in SW48 cells expressing <i>KRAS</i>-specific siRNAs. Multiple <i>KRAS</i> siRNA oligos and a pool efficiently suppressed KRAS expression showing that the siRNAs were on-target.</p>", "links"=>[], "tags"=>["KRAS Mutant Tumours Activating KRAS mutations", "molecule CDK 1 inhibitor", "type colorectal isogenic tumour cells", "CDK 1", "Synthetic Lethal Target", "master control", "acid position 12", "xenograft model", "CDK 1.", "siRNA screens", "tumour cells", "p.G 12V pG 12D p.G 12S", "CDK 1 inhibition", "acid position 13", "26 colorectal", "pancreatic tumour cell models", "p.G 13D KRAS mutations"], "article_id"=>2343586, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biotechnology", "Chemical Sciences not elsewhere classified", "Biological Sciences not elsewhere classified", "Developmental Biology", "Cancer", "Hematology"], "users"=>["Sara Costa-Cabral", "Rachel Brough", "Asha Konde", "Marieke Aarts", "James Campbell", "Eliana Marinari", "Jenna Riffell", "Alberto Bardelli", "Christopher Torrance", "Christopher J. Lord", "Alan Ashworth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0149099.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Characterization_of_LIM1215_isogenic_cell_lines_/2343586", "title"=>"Characterization of LIM1215 isogenic cell lines.", "pos_in_sequence"=>2, "defined_type"=>1, "published_date"=>"2016-02-16 07:56:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/3982183"], "description"=>"<p>(A) AT7519, (B) dinaciclib and (C) PD023309 median of drug-dose response curves of <i>KRAS</i> WT and mutant cells from a five-day cell viability assay to assess the KRAS selectivity of the CDK inhibitors in ten colorectal cell lines, four KRAS WT (black) and six mutant (pink) cell lines. (ns not-significant, Two-way ANOVA) Experimental conditions were repeated in triplicate. Error bars represent SEM. Only AT7519 and dinaciclib showed KRAS selectivity in the CRC cell lines.</p>", "links"=>[], "tags"=>["KRAS Mutant Tumours Activating KRAS mutations", "molecule CDK 1 inhibitor", "type colorectal isogenic tumour cells", "CDK 1", "Synthetic Lethal Target", "master control", "acid position 12", "xenograft model", "CDK 1.", "siRNA screens", "tumour cells", "p.G 12V pG 12D p.G 12S", "CDK 1 inhibition", "acid position 13", "26 colorectal", "pancreatic tumour cell models", "p.G 13D KRAS mutations"], "article_id"=>2343811, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biotechnology", "Chemical Sciences not elsewhere classified", "Biological Sciences not elsewhere classified", "Developmental Biology", "Cancer", "Hematology"], "users"=>["Sara Costa-Cabral", "Rachel Brough", "Asha Konde", "Marieke Aarts", "James Campbell", "Eliana Marinari", "Jenna Riffell", "Alberto Bardelli", "Christopher Torrance", "Christopher J. Lord", "Alan Ashworth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0149099.g007", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Response_to_three_second_generation_CDK_inhibitors_in_CRC_cell_lines_/2343811", "title"=>"Response to three second-generation CDK inhibitors in CRC cell lines.", "pos_in_sequence"=>8, "defined_type"=>1, "published_date"=>"2016-02-16 07:56:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/3982102"], "description"=>"<p>(A—C). CDK1 phosphorylation levels in KRAS mutant and WT cells as shown by Western blot analysis of total cell protein lysates from SW48 KRAS isogenic (A), non-isogenic pancreatic tumour cell lines (B) and non-isogenic colorectal cell lines (C). Western blots were probed for CDK1 (pThr161 CDK1 and total CDK1). β-actin detection was used as a loading control. (D and E) Bar graphs illustrating the percentage of cells in G1, S and G2/M cell cycle phases in SW48 KRAS WT or p.G12V mutant cell lines after AZD5438 exposure. SW48 KRAS WT (D) and p.G12V (E) were exposed to 0.3 μM AZD5438 or DMSO for 16, 24 and 48 hours after which cell cycle profiles were assessed by propidium iodide (PI) staining and flow cytometry. The KRAS p.G12V mutant cells showed a decrease in S and G2-fractions after exposure to AZD5438 when compared to control (DMSO) treated cells and to KRAS WT cells (AZD5438 and DMSO). (F—H) DNA synthesis in SW48 KRAS WT and p.G12V cell lines after AZD5438 exposure. (F) and (G) 5-ethynyl-2'-deoxyuridine (EDU)/ PI FACS plots in SW48 KRAS WT (F) and p.G12V mutant cells exposed to AZD5438 0.3 μM and 0.75 μM, or DMSO for 24 and 48 hours. After AZD5438 exposure, EDU/PI profiles were assessed by flow cytometry. EDU stained cells are represented in blue. (H) Bar graph illustrating the percentage of cells stained with EDU over time for both SW48 KRAS WT and p.G12V mutant cells. (I) Western blot illustrating the phosphorylation of Retinoblastoma protein (pRb) in SW48 KRAS WT and p.G12V mutant cell lines after AZD5438 exposure. Cells were exposed to AZD5438 for two hours after which total cell lysates were generated and western blotted as shown. Detection of β-Actin was used as a loading control. The levels of Rb phosphorylation on Ser807/811 were decreased in the KRAS p.G12V cells when compared to the WT cells, after AZD5438 2 hours exposure. (J) Western blot illustrating PARP1 cleavage in SW48 KRAS WT and p.G12V mutant cells after 72h of AZD5438 exposure. Cells were exposed to AZD5438 for two hours after which total cell lysates were generated and western blotted as shown. Exposure to camptothecin was used as a positive control.</p>", "links"=>[], "tags"=>["KRAS Mutant Tumours Activating KRAS mutations", "molecule CDK 1 inhibitor", "type colorectal isogenic tumour cells", "CDK 1", "Synthetic Lethal Target", "master control", "acid position 12", "xenograft model", "CDK 1.", "siRNA screens", "tumour cells", "p.G 12V pG 12D p.G 12S", "CDK 1 inhibition", "acid position 13", "26 colorectal", "pancreatic tumour cell models", "p.G 13D KRAS mutations"], "article_id"=>2343781, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biotechnology", "Chemical Sciences not elsewhere classified", "Biological Sciences not elsewhere classified", "Developmental Biology", "Cancer", "Hematology"], "users"=>["Sara Costa-Cabral", "Rachel Brough", "Asha Konde", "Marieke Aarts", "James Campbell", "Eliana Marinari", "Jenna Riffell", "Alberto Bardelli", "Christopher Torrance", "Christopher J. Lord", "Alan Ashworth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0149099.g006", "stats"=>{"downloads"=>2, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/CDK1_Is_a_Synthetic_Lethal_Target_for_KRAS_Mutant_Tumours_Fig_6/2343781", "title"=>"CDK1 Is a Synthetic Lethal Target for KRAS Mutant Tumours - Fig 6", "pos_in_sequence"=>7, "defined_type"=>1, "published_date"=>"2016-02-16 07:56:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/3982009"], "description"=>"<p>(A) and (B) Waterfall and scatter plots, respectively, of a panel of non-isogenic colorectal cell lines showing a statistically significant difference in surviving fraction in response to KRAS depletion by siRNA between the <i>KRAS</i> WT (black) and mutant (pink) cell lines (P<0.0001, Student’s t-test for comparison between <i>KRAS</i> mutant and WT cell lines). (C) and (D) Waterfall and scatter plots, respectively, showing the surviving fractions of a panel of non-isogenic CRC cell lines after CDK1 depletion by siRNA. Black bars represent <i>KRAS</i> WT cell lines and pink bars represent <i>KRAS</i> mutant cell lines (ns, not statistically significant, Student’s t-test for comparison between <i>KRAS</i> mutant and WT cell lines). (E) Waterfall plot of the same CRC cell line panel as described in 4C, but with the <i>KRAS</i> WT cells divided into <i>KRAS</i> WT/<i>BRAF</i> WT (black), <i>KRAS</i> WT/<i>BRAF</i> mutant (green). (F) Scatter plot of the panel of CRC non-isogenic cell lines, without the <i>KRAS</i> WT/<i>BRAF</i> mutant cells, showing that the difference between the <i>KRAS</i> mutant (pink) and WT (black) cells to CDK1 depletion by siRNA is statistically significant (**P>0.01, Student’s t-test for comparison between <i>KRAS</i> mutant and WT cell lines.). (G) Scatter plot demonstrating a statistically significant difference in survival between <i>KRAS</i> WT/<i>BRAF</i> WT (black) and <i>KRAS</i> WT/<i>BRAF</i> mutants (green) after CDK1 depletion (*P>0.05, Student’s t-test for comparison between <i>BRAF</i> mutant and WT cell lines.). (H) Waterfall plot of pancreatic cell lines showing that the <i>KRAS</i> mutant cells (pink) were significantly more sensitive to KRAS depletion by siRNA than the <i>KRAS</i> WT cells (black) (***P<0.001, Student’s t-test for comparison between each <i>KRAS</i> mutant cell lines and the WT cell line). (I) Waterfall plot of pancreatic cell lines showing that the <i>KRAS</i> mutant cells (pink) were significantly more sensitive to CDK1 depletion by siRNA than the <i>KRAS</i> WT cells (black) (***P<0.001, Student’s t-test for comparison between each <i>KRAS</i> mutant cell lines and the WT cell line). Surviving fractions normalized to siControl1 transfected cells. Error bars represent SEM from three independent experiments.</p>", "links"=>[], "tags"=>["KRAS Mutant Tumours Activating KRAS mutations", "molecule CDK 1 inhibitor", "type colorectal isogenic tumour cells", "CDK 1", "Synthetic Lethal Target", "master control", "acid position 12", "xenograft model", "CDK 1.", "siRNA screens", "tumour cells", "p.G 12V pG 12D p.G 12S", "CDK 1 inhibition", "acid position 13", "26 colorectal", "pancreatic tumour cell models", "p.G 13D KRAS mutations"], "article_id"=>2343718, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biotechnology", "Chemical Sciences not elsewhere classified", "Biological Sciences not elsewhere classified", "Developmental Biology", "Cancer", "Hematology"], "users"=>["Sara Costa-Cabral", "Rachel Brough", "Asha Konde", "Marieke Aarts", "James Campbell", "Eliana Marinari", "Jenna Riffell", "Alberto Bardelli", "Christopher Torrance", "Christopher J. Lord", "Alan Ashworth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0149099.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Effects_of_CDK1_depletion_in_non_isogenic_KRAS_mutant_cell_models_/2343718", "title"=>"Effects of CDK1 depletion in non-isogenic KRAS mutant cell models.", "pos_in_sequence"=>5, "defined_type"=>1, "published_date"=>"2016-02-16 07:56:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/3982054"], "description"=>"<p>(A) Exposure of SW48 isogenic cell lines to RO-3306 in a fifteen-day colony formation assay. (B) Exposure of SW48 isogenic cell lines to inhibitor AZD5438, in a fifteen-day colony formation assay. (C) Drug-dose response curves of CRC cells after AZD5438 exposure in a fifteen-day colony formation assay. ****P<0.0001, Two-way ANOVA. Error bars represent SEM of three technical replicates. All the experiments were performed two independent times with three technical replicates.</p>", "links"=>[], "tags"=>["KRAS Mutant Tumours Activating KRAS mutations", "molecule CDK 1 inhibitor", "type colorectal isogenic tumour cells", "CDK 1", "Synthetic Lethal Target", "master control", "acid position 12", "xenograft model", "CDK 1.", "siRNA screens", "tumour cells", "p.G 12V pG 12D p.G 12S", "CDK 1 inhibition", "acid position 13", "26 colorectal", "pancreatic tumour cell models", "p.G 13D KRAS mutations"], "article_id"=>2343751, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biotechnology", "Chemical Sciences not elsewhere classified", "Biological Sciences not elsewhere classified", "Developmental Biology", "Cancer", "Hematology"], "users"=>["Sara Costa-Cabral", "Rachel Brough", "Asha Konde", "Marieke Aarts", "James Campbell", "Eliana Marinari", "Jenna Riffell", "Alberto Bardelli", "Christopher Torrance", "Christopher J. Lord", "Alan Ashworth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0149099.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/CDK_inhibitors_sensitivity_profile_in_SW48_KRAS_isogenic_cell_lines_/2343751", "title"=>"CDK inhibitors sensitivity profile in SW48 KRAS isogenic cell lines.", "pos_in_sequence"=>6, "defined_type"=>1, "published_date"=>"2016-02-16 07:56:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/3982261"], "description"=>"<p>The table shows the median Z scores for the KRAS WT and mutant cells and the respective Delta median Z scores.</p>", "links"=>[], "tags"=>["KRAS Mutant Tumours Activating KRAS mutations", "molecule CDK 1 inhibitor", "type colorectal isogenic tumour cells", "CDK 1", "Synthetic Lethal Target", "master control", "acid position 12", "xenograft model", "CDK 1.", "siRNA screens", "tumour cells", "p.G 12V pG 12D p.G 12S", "CDK 1 inhibition", "acid position 13", "26 colorectal", "pancreatic tumour cell models", "p.G 13D KRAS mutations"], "article_id"=>2343856, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biotechnology", "Chemical Sciences not elsewhere classified", "Biological Sciences not elsewhere classified", "Developmental Biology", "Cancer", "Hematology"], "users"=>["Sara Costa-Cabral", "Rachel Brough", "Asha Konde", "Marieke Aarts", "James Campbell", "Eliana Marinari", "Jenna Riffell", "Alberto Bardelli", "Christopher Torrance", "Christopher J. Lord", "Alan Ashworth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0149099.t001", "stats"=>{"downloads"=>2, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Candidate_i_KRAS_i_synthetic_lethal_genes_identified_in_LIM1215_KRAS_isogenic_cell_lines_siRNA_screens_/2343856", "title"=>"Candidate <i>KRAS</i> synthetic lethal genes identified in LIM1215 KRAS isogenic cell lines siRNA screens.", "pos_in_sequence"=>10, "defined_type"=>3, "published_date"=>"2016-02-16 07:56:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/3981892"], "description"=>"<p>(A) Schematic describing the screen format. LIM1215 cells plated in 384 well plates were transfected with siRNA. Each transfection plate contained 300 experimental siRNAs supplemented with wells of non-targeting siCONTROL (siCON) and siRNA targeting PLK1 (positive control). Transfected cells were divided into three replica plates. Cell viability was assessed after six days using CellTiter-Glo Luminescent Cell Viability Assay (Promega). (B) Heatmap of siRNA z-scores for 15 screens used in the analysis. The rows of the heatmap correspond to siRNAs and are ordered by the difference in the KRAS mutant and non-mutant group median z-scores. The heatmap inset shows the six siRNAs selected for andditional analyses. These siRNAs were selected because they caused reduced viability in the KRAS mutant isogenic models (median z ≤ -2) but not in the WT and neo cell lines (median z ≥ -1).</p>", "links"=>[], "tags"=>["KRAS Mutant Tumours Activating KRAS mutations", "molecule CDK 1 inhibitor", "type colorectal isogenic tumour cells", "CDK 1", "Synthetic Lethal Target", "master control", "acid position 12", "xenograft model", "CDK 1.", "siRNA screens", "tumour cells", "p.G 12V pG 12D p.G 12S", "CDK 1 inhibition", "acid position 13", "26 colorectal", "pancreatic tumour cell models", "p.G 13D KRAS mutations"], "article_id"=>2343634, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biotechnology", "Chemical Sciences not elsewhere classified", "Biological Sciences not elsewhere classified", "Developmental Biology", "Cancer", "Hematology"], "users"=>["Sara Costa-Cabral", "Rachel Brough", "Asha Konde", "Marieke Aarts", "James Campbell", "Eliana Marinari", "Jenna Riffell", "Alberto Bardelli", "Christopher Torrance", "Christopher J. Lord", "Alan Ashworth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0149099.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Identification_of_CDK1_as_a_KRAS_synthetic_lethality_using_functional_genomic_screens_in_the_LIM1215_KRAS_isogenic_models_/2343634", "title"=>"Identification of CDK1 as a KRAS synthetic lethality using functional genomic screens in the LIM1215 KRAS isogenic models.", "pos_in_sequence"=>3, "defined_type"=>1, "published_date"=>"2016-02-16 07:56:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/3982213"], "description"=>"<p>KRAS mutant xenografts were treated with vehicle (DMSO in black) or AZD5438 (20mg/kg/day (in pink)). (A) Mean of increase in tumour volume relative to initial tumour volume. A one-way ANOVA was performed to compare both arms and the difference in the SW620 xenografts was statistically significant (p = 0.017). (B) Survival curves showing a statistically significant difference between the treated and vehicle arms, where the mice in the drug arm had an increase in overall survival using a Log-rank Mantel-Cox test (p = 0.0018 in SW620 xenografts). (C) Average final tumour weight. There is a significant difference between the vehicle and treatment arms (**p < 0.01, t-test). Error bars represent SEM. (D) Photograph of a mouse treated with AZD5438, where the tumour disappeared completely, after 37 days of treatment.</p>", "links"=>[], "tags"=>["KRAS Mutant Tumours Activating KRAS mutations", "molecule CDK 1 inhibitor", "type colorectal isogenic tumour cells", "CDK 1", "Synthetic Lethal Target", "master control", "acid position 12", "xenograft model", "CDK 1.", "siRNA screens", "tumour cells", "p.G 12V pG 12D p.G 12S", "CDK 1 inhibition", "acid position 13", "26 colorectal", "pancreatic tumour cell models", "p.G 13D KRAS mutations"], "article_id"=>2343832, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biotechnology", "Chemical Sciences not elsewhere classified", "Biological Sciences not elsewhere classified", "Developmental Biology", "Cancer", "Hematology"], "users"=>["Sara Costa-Cabral", "Rachel Brough", "Asha Konde", "Marieke Aarts", "James Campbell", "Eliana Marinari", "Jenna Riffell", "Alberto Bardelli", "Christopher Torrance", "Christopher J. Lord", "Alan Ashworth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0149099.g008", "stats"=>{"downloads"=>2, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_i_In_vivo_i_efficacy_of_AZD5438_in_SW620_cell_xenografts_/2343832", "title"=>"<i>In vivo</i> efficacy of AZD5438 in SW620 cell xenografts.", "pos_in_sequence"=>9, "defined_type"=>1, "published_date"=>"2016-02-16 07:56:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/3981943"], "description"=>"<p>(A) GTP-RAS assay showing the RAS activation status of SW48 KRAS isogenic cell lines. (B) KRAS dependence in the SW48 KRAS isogenic cell lines (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, Student’s t-test for comparison between each <i>KRAS</i> mutant and the WT cell lines). (C) CDK1-specific siRNAs suppress CDK1 expression. Cell viability after CDK1 depletion in SW48 isogenic KRAS cell lines (ns, not statistically significant, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, Student’s t-test for comparison between each <i>KRAS</i> mutant and the WT cell lines). Error bars represent SEM from three independent experiments. (D) Western blot of CDK1 in SW48 parental cells expressing CDK1-specific siRNAs.</p>", "links"=>[], "tags"=>["KRAS Mutant Tumours Activating KRAS mutations", "molecule CDK 1 inhibitor", "type colorectal isogenic tumour cells", "CDK 1", "Synthetic Lethal Target", "master control", "acid position 12", "xenograft model", "CDK 1.", "siRNA screens", "tumour cells", "p.G 12V pG 12D p.G 12S", "CDK 1 inhibition", "acid position 13", "26 colorectal", "pancreatic tumour cell models", "p.G 13D KRAS mutations"], "article_id"=>2343676, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biotechnology", "Chemical Sciences not elsewhere classified", "Biological Sciences not elsewhere classified", "Developmental Biology", "Cancer", "Hematology"], "users"=>["Sara Costa-Cabral", "Rachel Brough", "Asha Konde", "Marieke Aarts", "James Campbell", "Eliana Marinari", "Jenna Riffell", "Alberto Bardelli", "Christopher Torrance", "Christopher J. Lord", "Alan Ashworth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0149099.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Validation_of_the_CDK1_hit_from_the_LIM1215_siRNA_screen_in_SW48_isogenic_cell_lines_/2343676", "title"=>"Validation of the CDK1 hit from the LIM1215 siRNA screen in SW48 isogenic cell lines.", "pos_in_sequence"=>4, "defined_type"=>1, "published_date"=>"2016-02-16 07:56:30"}

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Relative Metric

{"start_date"=>"2016-01-01T00:00:00Z", "end_date"=>"2016-12-31T00:00:00Z", "subject_areas"=>[]}
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