The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets
The development of molecularly targeted anticancer agents relies on large panels of tumour-specific preclinical models closely recapitulating the molecular heterogeneity observed in patients. Here we describe the mutational and gene expression analyses of 151 colorectal cancer (CRC) cell lines. We f...
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| Veröffentlicht in: | Nature communications 2015-04, Vol.6 (1), p.7002-7002, Article 7002 |
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| creator | Medico, Enzo Russo, Mariangela Picco, Gabriele Cancelliere, Carlotta Valtorta, Emanuele Corti, Giorgio Buscarino, Michela Isella, Claudio Lamba, Simona Martinoglio, Barbara Veronese, Silvio Siena, Salvatore Sartore-Bianchi, Andrea Beccuti, Marco Mottolese, Marcella Linnebacher, Michael Cordero, Francesca Di Nicolantonio, Federica Bardelli, Alberto |
| description | The development of molecularly targeted anticancer agents relies on large panels of tumour-specific preclinical models closely recapitulating the molecular heterogeneity observed in patients. Here we describe the mutational and gene expression analyses of 151 colorectal cancer (CRC) cell lines. We find that the whole spectrum of CRC molecular and transcriptional subtypes, previously defined in patients, is represented in this cell line compendium. Transcriptional outlier analysis identifies
RAS/BRAF
wild-type cells, resistant to EGFR blockade, functionally and pharmacologically addicted to kinase genes including ALK, FGFR2, NTRK1/2 and RET. The same genes are present as expression outliers in CRC patient samples. Genomic rearrangements (translocations) involving the
ALK
and
NTRK1
genes are associated with the overexpression of the corresponding proteins in CRC specimens. The approach described here can be used to pinpoint CRCs with exquisite dependencies to individual kinases for which clinically approved drugs are already available.
Precision oncology relies on model systems that reflect the genomic heterogeneity of human cancers. Here the authors characterize a panel of 151 colorectal cancer cell lines with respect to genetic mutations, expression profiles and drug sensitivity to identify new therapeutic targets. |
| doi_str_mv | 10.1038/ncomms8002 |
| format | Article |
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RAS/BRAF
wild-type cells, resistant to EGFR blockade, functionally and pharmacologically addicted to kinase genes including ALK, FGFR2, NTRK1/2 and RET. The same genes are present as expression outliers in CRC patient samples. Genomic rearrangements (translocations) involving the
ALK
and
NTRK1
genes are associated with the overexpression of the corresponding proteins in CRC specimens. The approach described here can be used to pinpoint CRCs with exquisite dependencies to individual kinases for which clinically approved drugs are already available.
Precision oncology relies on model systems that reflect the genomic heterogeneity of human cancers. Here the authors characterize a panel of 151 colorectal cancer cell lines with respect to genetic mutations, expression profiles and drug sensitivity to identify new therapeutic targets.</description><identifier>ISSN: 2041-1723</identifier><identifier>EISSN: 2041-1723</identifier><identifier>DOI: 10.1038/ncomms8002</identifier><identifier>PMID: 25926053</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/208/199 ; 631/337/572 ; 631/67/1059/602 ; 631/67/1504/1885 ; Cell Line, Tumor ; Cetuximab ; Colorectal cancer ; Colorectal Neoplasms - enzymology ; Colorectal Neoplasms - genetics ; Genes, erbB-1 ; Genetic Heterogeneity ; Humanities and Social Sciences ; Humans ; Molecular Targeted Therapy ; multidisciplinary ; Proto-Oncogene Proteins c-ret - metabolism ; Receptor Protein-Tyrosine Kinases - genetics ; Receptor Protein-Tyrosine Kinases - metabolism ; Receptor, Epidermal Growth Factor - antagonists & inhibitors ; Receptor, Fibroblast Growth Factor, Type 2 - metabolism ; Science ; Science (multidisciplinary)</subject><ispartof>Nature communications, 2015-04, Vol.6 (1), p.7002-7002, Article 7002</ispartof><rights>Springer Nature Limited 2015</rights><rights>Copyright Nature Publishing Group Apr 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c453t-f36506676c137e580e6736cab5c34188bb1c27e38f835a191fbe2ab145f925083</citedby><cites>FETCH-LOGICAL-c453t-f36506676c137e580e6736cab5c34188bb1c27e38f835a191fbe2ab145f925083</cites><orcidid>0000-0001-6379-4117 ; 0000-0001-9618-2010 ; 0000000196182010 ; 0000000163794117</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/ncomms8002$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://doi.org/10.1038/ncomms8002$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,860,27901,27902,41096,42165,51551</link.rule.ids><linktorsrc>$$Uhttps://doi.org/10.1038/ncomms8002$$EView_record_in_Springer_Nature$$FView_record_in_$$GSpringer_Nature</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25926053$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Medico, Enzo</creatorcontrib><creatorcontrib>Russo, Mariangela</creatorcontrib><creatorcontrib>Picco, Gabriele</creatorcontrib><creatorcontrib>Cancelliere, Carlotta</creatorcontrib><creatorcontrib>Valtorta, Emanuele</creatorcontrib><creatorcontrib>Corti, Giorgio</creatorcontrib><creatorcontrib>Buscarino, Michela</creatorcontrib><creatorcontrib>Isella, Claudio</creatorcontrib><creatorcontrib>Lamba, Simona</creatorcontrib><creatorcontrib>Martinoglio, Barbara</creatorcontrib><creatorcontrib>Veronese, Silvio</creatorcontrib><creatorcontrib>Siena, Salvatore</creatorcontrib><creatorcontrib>Sartore-Bianchi, Andrea</creatorcontrib><creatorcontrib>Beccuti, Marco</creatorcontrib><creatorcontrib>Mottolese, Marcella</creatorcontrib><creatorcontrib>Linnebacher, Michael</creatorcontrib><creatorcontrib>Cordero, Francesca</creatorcontrib><creatorcontrib>Di Nicolantonio, Federica</creatorcontrib><creatorcontrib>Bardelli, Alberto</creatorcontrib><title>The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets</title><title>Nature communications</title><addtitle>Nat Commun</addtitle><addtitle>Nat Commun</addtitle><description>The development of molecularly targeted anticancer agents relies on large panels of tumour-specific preclinical models closely recapitulating the molecular heterogeneity observed in patients. Here we describe the mutational and gene expression analyses of 151 colorectal cancer (CRC) cell lines. We find that the whole spectrum of CRC molecular and transcriptional subtypes, previously defined in patients, is represented in this cell line compendium. Transcriptional outlier analysis identifies
RAS/BRAF
wild-type cells, resistant to EGFR blockade, functionally and pharmacologically addicted to kinase genes including ALK, FGFR2, NTRK1/2 and RET. The same genes are present as expression outliers in CRC patient samples. Genomic rearrangements (translocations) involving the
ALK
and
NTRK1
genes are associated with the overexpression of the corresponding proteins in CRC specimens. The approach described here can be used to pinpoint CRCs with exquisite dependencies to individual kinases for which clinically approved drugs are already available.
Precision oncology relies on model systems that reflect the genomic heterogeneity of human cancers. Here the authors characterize a panel of 151 colorectal cancer cell lines with respect to genetic mutations, expression profiles and drug sensitivity to identify new therapeutic targets.</description><subject>631/208/199</subject><subject>631/337/572</subject><subject>631/67/1059/602</subject><subject>631/67/1504/1885</subject><subject>Cell Line, Tumor</subject><subject>Cetuximab</subject><subject>Colorectal cancer</subject><subject>Colorectal Neoplasms - enzymology</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Genes, erbB-1</subject><subject>Genetic Heterogeneity</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Molecular Targeted Therapy</subject><subject>multidisciplinary</subject><subject>Proto-Oncogene Proteins c-ret - metabolism</subject><subject>Receptor Protein-Tyrosine Kinases - genetics</subject><subject>Receptor Protein-Tyrosine Kinases - metabolism</subject><subject>Receptor, Epidermal Growth Factor - 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unveils clinically actionable kinase targets</atitle><jtitle>Nature communications</jtitle><stitle>Nat Commun</stitle><addtitle>Nat Commun</addtitle><date>2015-04-30</date><risdate>2015</risdate><volume>6</volume><issue>1</issue><spage>7002</spage><epage>7002</epage><pages>7002-7002</pages><artnum>7002</artnum><issn>2041-1723</issn><eissn>2041-1723</eissn><abstract>The development of molecularly targeted anticancer agents relies on large panels of tumour-specific preclinical models closely recapitulating the molecular heterogeneity observed in patients. Here we describe the mutational and gene expression analyses of 151 colorectal cancer (CRC) cell lines. We find that the whole spectrum of CRC molecular and transcriptional subtypes, previously defined in patients, is represented in this cell line compendium. Transcriptional outlier analysis identifies
RAS/BRAF
wild-type cells, resistant to EGFR blockade, functionally and pharmacologically addicted to kinase genes including ALK, FGFR2, NTRK1/2 and RET. The same genes are present as expression outliers in CRC patient samples. Genomic rearrangements (translocations) involving the
ALK
and
NTRK1
genes are associated with the overexpression of the corresponding proteins in CRC specimens. The approach described here can be used to pinpoint CRCs with exquisite dependencies to individual kinases for which clinically approved drugs are already available.
Precision oncology relies on model systems that reflect the genomic heterogeneity of human cancers. Here the authors characterize a panel of 151 colorectal cancer cell lines with respect to genetic mutations, expression profiles and drug sensitivity to identify new therapeutic targets.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>25926053</pmid><doi>10.1038/ncomms8002</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0001-6379-4117</orcidid><orcidid>https://orcid.org/0000-0001-9618-2010</orcidid><orcidid>https://orcid.org/0000000196182010</orcidid><orcidid>https://orcid.org/0000000163794117</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Springer Nature OA/Free Journals |
| subjects | 631/208/199 631/337/572 631/67/1059/602 631/67/1504/1885 Cell Line, Tumor Cetuximab Colorectal cancer Colorectal Neoplasms - enzymology Colorectal Neoplasms - genetics Genes, erbB-1 Genetic Heterogeneity Humanities and Social Sciences Humans Molecular Targeted Therapy multidisciplinary Proto-Oncogene Proteins c-ret - metabolism Receptor Protein-Tyrosine Kinases - genetics Receptor Protein-Tyrosine Kinases - metabolism Receptor, Epidermal Growth Factor - antagonists & inhibitors Receptor, Fibroblast Growth Factor, Type 2 - metabolism Science Science (multidisciplinary) |
| title | The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets |
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