The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

Enzo Medico; Mariangela Russo; Gabriele Picco; Carlotta Cancelliere; Emanuele Valtorta; Giorgio Corti; Michela Buscarino; Claudio Isella; Simona Lamba; Barbara Martinoglio; Silvio Veronese; Salvatore Siena; Andrea Sartore-Bianchi; Marco Beccuti; Marcella Mottolese; Michael Linnebacher; Francesca Cordero; Federica Di Nicolantonio; Alberto Bardelli

doi:10.1038/ncomms8002

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

Enzo Medico, Mariangela Russo, Gabriele Picco, Carlotta Cancelliere, Emanuele Valtorta, Giorgio Corti, Michela Buscarino, Claudio Isella, Simona Lamba, Barbara Martinoglio, Silvio Veronese, Salvatore Siena, Andrea Sartore-Bianchi, Marco Beccuti, Marcella Mottolese, Michael Linnebacher, Francesca Cordero, Federica Di Nicolantonio, Alberto Bardelli

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	7002
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8002
Publication status	Published - Apr 30 2015

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Chemistry(all)
Physics and Astronomy(all)

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Medico, E., Russo, M., Picco, G., Cancelliere, C., Valtorta, E., Corti, G., Buscarino, M., Isella, C., Lamba, S., Martinoglio, B., Veronese, S., Siena, S., Sartore-Bianchi, A., Beccuti, M., Mottolese, M., Linnebacher, M., Cordero, F., Di Nicolantonio, F., & Bardelli, A. (2015). The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets. Nature Communications, 6, [7002]. https://doi.org/10.1038/ncomms8002

Medico, E, Russo, M, Picco, G, Cancelliere, C, Valtorta, E, Corti, G, Buscarino, M, Isella, C , Lamba, S , Martinoglio, B, Veronese, S, Siena, S, Sartore-Bianchi, A, Beccuti, M, Mottolese, M, Linnebacher, M, Cordero, F, Di Nicolantonio, F & Bardelli, A 2015, 'The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets', Nature Communications, vol. 6, 7002. https://doi.org/10.1038/ncomms8002

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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.",

author = "Enzo Medico and Mariangela Russo and Gabriele Picco and Carlotta Cancelliere and Emanuele Valtorta and Giorgio Corti and Michela Buscarino and Claudio Isella and Simona Lamba and Barbara Martinoglio and Silvio Veronese and Salvatore Siena and Andrea Sartore-Bianchi and Marco Beccuti and Marcella Mottolese and Michael Linnebacher and Francesca Cordero and {Di Nicolantonio}, Federica and Alberto Bardelli",

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AU - Medico, Enzo

AU - Russo, Mariangela

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AU - Valtorta, Emanuele

AU - Corti, Giorgio

AU - Buscarino, Michela

AU - Isella, Claudio

AU - Lamba, Simona

AU - Martinoglio, Barbara

AU - Veronese, Silvio

AU - Siena, Salvatore

AU - Sartore-Bianchi, Andrea

AU - Beccuti, Marco

AU - Mottolese, Marcella

AU - Linnebacher, Michael

AU - Cordero, Francesca

AU - Di Nicolantonio, Federica

AU - Bardelli, Alberto

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AB - 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.

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The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

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