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Integrated functional, gene expression and genomic analysis for the identification of cancer targets
The majority of new drug approvals for cancer are based on existing therapeutic targets. One approach to the identification of novel targets is to perform high-throughput RNA interference (RNAi) cellular viability screens. We describe a novel approach combining RNAi screening in multiple cell lines...
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| Published in: | PloS one 2009-04, Vol.4 (4), p.e5120-e5120 |
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| creator | Iorns, Elizabeth Lord, Christopher J Grigoriadis, Anita McDonald, Sarah Fenwick, Kerry Mackay, Alan Mein, Charles A Natrajan, Rachael Savage, Kay Tamber, Narinder Reis-Filho, Jorge S Turner, Nicholas C Ashworth, Alan |
| description | The majority of new drug approvals for cancer are based on existing therapeutic targets. One approach to the identification of novel targets is to perform high-throughput RNA interference (RNAi) cellular viability screens. We describe a novel approach combining RNAi screening in multiple cell lines with gene expression and genomic profiling to identify novel cancer targets. We performed parallel RNAi screens in multiple cancer cell lines to identify genes that are essential for viability in some cell lines but not others, suggesting that these genes constitute key drivers of cellular survival in specific cancer cells. This approach was verified by the identification of PIK3CA, silencing of which was selectively lethal to the MCF7 cell line, which harbours an activating oncogenic PIK3CA mutation. We combined our functional RNAi approach with gene expression and genomic analysis, allowing the identification of several novel kinases, including WEE1, that are essential for viability only in cell lines that have an elevated level of expression of this kinase. Furthermore, we identified a subset of breast tumours that highly express WEE1 suggesting that WEE1 could be a novel therapeutic target in breast cancer. In conclusion, this strategy represents a novel and effective strategy for the identification of functionally important therapeutic targets in cancer. |
| doi_str_mv | 10.1371/journal.pone.0005120 |
| format | article |
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One approach to the identification of novel targets is to perform high-throughput RNA interference (RNAi) cellular viability screens. We describe a novel approach combining RNAi screening in multiple cell lines with gene expression and genomic profiling to identify novel cancer targets. We performed parallel RNAi screens in multiple cancer cell lines to identify genes that are essential for viability in some cell lines but not others, suggesting that these genes constitute key drivers of cellular survival in specific cancer cells. This approach was verified by the identification of PIK3CA, silencing of which was selectively lethal to the MCF7 cell line, which harbours an activating oncogenic PIK3CA mutation. We combined our functional RNAi approach with gene expression and genomic analysis, allowing the identification of several novel kinases, including WEE1, that are essential for viability only in cell lines that have an elevated level of expression of this kinase. Furthermore, we identified a subset of breast tumours that highly express WEE1 suggesting that WEE1 could be a novel therapeutic target in breast cancer. In conclusion, this strategy represents a novel and effective strategy for the identification of functionally important therapeutic targets in cancer.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0005120</identifier><identifier>PMID: 19357772</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Biotechnology ; Breast cancer ; Cancer ; Cancer genetics ; Cell Cycle Proteins - genetics ; Cell Line, Tumor ; Cell survival ; Class I Phosphatidylinositol 3-Kinases ; Drug approval ; Drug Screening Assays, Antitumor ; Endocrine therapy ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Genes ; Genetic aspects ; Genetic research ; Genetics and Genomics/Cancer Genetics ; Genetics and Genomics/Functional Genomics ; Genome ; Genomes ; Genomic analysis ; Genomics ; Health aspects ; Humans ; Identification ; Kinases ; Ligands ; Lung cancer ; Medical research ; Medical screening ; Molecular Sequence Data ; Multiple myeloma ; Mutation ; Neoplasm Proteins - genetics ; Neoplasms - genetics ; Neoplasms - therapy ; Nuclear Proteins - genetics ; Oligonucleotide Array Sequence Analysis ; Oncology ; Phosphatidylinositol 3-Kinases - genetics ; Phosphotransferases ; Protein-Tyrosine Kinases - genetics ; Ribonucleic acid ; RNA ; RNA Interference ; RNA, Small Interfering - genetics ; RNA, Small Interfering - metabolism ; RNA-mediated interference ; Target recognition ; Tumor cell lines ; Tumors</subject><ispartof>PloS one, 2009-04, Vol.4 (4), p.e5120-e5120</ispartof><rights>COPYRIGHT 2009 Public Library of Science</rights><rights>2009 Iorns et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Iorns et al. 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c693t-8245ead761e2224334f6f48c59cf6e2d16b6ad3e23ae05e39f17449031f2e0893</citedby><cites>FETCH-LOGICAL-c693t-8245ead761e2224334f6f48c59cf6e2d16b6ad3e23ae05e39f17449031f2e0893</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1290668284/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1290668284?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19357772$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ouchi, Toru</contributor><creatorcontrib>Iorns, Elizabeth</creatorcontrib><creatorcontrib>Lord, Christopher J</creatorcontrib><creatorcontrib>Grigoriadis, Anita</creatorcontrib><creatorcontrib>McDonald, Sarah</creatorcontrib><creatorcontrib>Fenwick, Kerry</creatorcontrib><creatorcontrib>Mackay, Alan</creatorcontrib><creatorcontrib>Mein, Charles A</creatorcontrib><creatorcontrib>Natrajan, Rachael</creatorcontrib><creatorcontrib>Savage, Kay</creatorcontrib><creatorcontrib>Tamber, Narinder</creatorcontrib><creatorcontrib>Reis-Filho, Jorge S</creatorcontrib><creatorcontrib>Turner, Nicholas C</creatorcontrib><creatorcontrib>Ashworth, Alan</creatorcontrib><title>Integrated functional, gene expression and genomic analysis for the identification of cancer targets</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The majority of new drug approvals for cancer are based on existing therapeutic targets. 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In conclusion, this strategy represents a novel and effective strategy for the identification of functionally important therapeutic targets in cancer.</description><subject>Analysis</subject><subject>Biotechnology</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cancer genetics</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Cell Line, Tumor</subject><subject>Cell survival</subject><subject>Class I Phosphatidylinositol 3-Kinases</subject><subject>Drug approval</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Endocrine therapy</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic research</subject><subject>Genetics and Genomics/Cancer Genetics</subject><subject>Genetics and Genomics/Functional Genomics</subject><subject>Genome</subject><subject>Genomes</subject><subject>Genomic analysis</subject><subject>Genomics</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Identification</subject><subject>Kinases</subject><subject>Ligands</subject><subject>Lung cancer</subject><subject>Medical research</subject><subject>Medical screening</subject><subject>Molecular Sequence Data</subject><subject>Multiple myeloma</subject><subject>Mutation</subject><subject>Neoplasm Proteins - 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One approach to the identification of novel targets is to perform high-throughput RNA interference (RNAi) cellular viability screens. We describe a novel approach combining RNAi screening in multiple cell lines with gene expression and genomic profiling to identify novel cancer targets. We performed parallel RNAi screens in multiple cancer cell lines to identify genes that are essential for viability in some cell lines but not others, suggesting that these genes constitute key drivers of cellular survival in specific cancer cells. This approach was verified by the identification of PIK3CA, silencing of which was selectively lethal to the MCF7 cell line, which harbours an activating oncogenic PIK3CA mutation. We combined our functional RNAi approach with gene expression and genomic analysis, allowing the identification of several novel kinases, including WEE1, that are essential for viability only in cell lines that have an elevated level of expression of this kinase. Furthermore, we identified a subset of breast tumours that highly express WEE1 suggesting that WEE1 could be a novel therapeutic target in breast cancer. In conclusion, this strategy represents a novel and effective strategy for the identification of functionally important therapeutic targets in cancer.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>19357772</pmid><doi>10.1371/journal.pone.0005120</doi><tpages>e5120</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2009-04, Vol.4 (4), p.e5120-e5120 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1290668284 |
| source | Publicly Available Content Database (Proquest) (PQ_SDU_P3); PubMed Central Free |
| subjects | Analysis Biotechnology Breast cancer Cancer Cancer genetics Cell Cycle Proteins - genetics Cell Line, Tumor Cell survival Class I Phosphatidylinositol 3-Kinases Drug approval Drug Screening Assays, Antitumor Endocrine therapy Gene expression Gene Expression Profiling Gene Expression Regulation, Neoplastic Genes Genetic aspects Genetic research Genetics and Genomics/Cancer Genetics Genetics and Genomics/Functional Genomics Genome Genomes Genomic analysis Genomics Health aspects Humans Identification Kinases Ligands Lung cancer Medical research Medical screening Molecular Sequence Data Multiple myeloma Mutation Neoplasm Proteins - genetics Neoplasms - genetics Neoplasms - therapy Nuclear Proteins - genetics Oligonucleotide Array Sequence Analysis Oncology Phosphatidylinositol 3-Kinases - genetics Phosphotransferases Protein-Tyrosine Kinases - genetics Ribonucleic acid RNA RNA Interference RNA, Small Interfering - genetics RNA, Small Interfering - metabolism RNA-mediated interference Target recognition Tumor cell lines Tumors |
| title | Integrated functional, gene expression and genomic analysis for the identification of cancer targets |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-02T11%3A04%3A22IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Integrated%20functional,%20gene%20expression%20and%20genomic%20analysis%20for%20the%20identification%20of%20cancer%20targets&rft.jtitle=PloS%20one&rft.au=Iorns,%20Elizabeth&rft.date=2009-04-09&rft.volume=4&rft.issue=4&rft.spage=e5120&rft.epage=e5120&rft.pages=e5120-e5120&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0005120&rft_dat=%3Cgale_plos_%3EA473258027%3C/gale_plos_%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c693t-8245ead761e2224334f6f48c59cf6e2d16b6ad3e23ae05e39f17449031f2e0893%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1290668284&rft_id=info:pmid/19357772&rft_galeid=A473258027&rfr_iscdi=true |