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 () and Alberto Bardelli ()
Additional contact information
Enzo Medico: University of Torino
Mariangela Russo: University of Torino
Gabriele Picco: University of Torino
Carlotta Cancelliere: Candiolo Cancer Institute—FPO, IRCCS
Emanuele Valtorta: Niguarda Cancer Center, Ospedale Niguarda Ca’ Granda
Giorgio Corti: Candiolo Cancer Institute—FPO, IRCCS
Michela Buscarino: Candiolo Cancer Institute—FPO, IRCCS
Claudio Isella: University of Torino
Simona Lamba: University of Torino
Barbara Martinoglio: Candiolo Cancer Institute—FPO, IRCCS
Silvio Veronese: Niguarda Cancer Center, Ospedale Niguarda Ca’ Granda
Salvatore Siena: Niguarda Cancer Center, Ospedale Niguarda Ca’ Granda
Andrea Sartore-Bianchi: Niguarda Cancer Center, Ospedale Niguarda Ca’ Granda
Marco Beccuti: University of Torino
Marcella Mottolese: S.C. Anatomia Patologica, Istituto Nazionale Tumori Regina Elena
Michael Linnebacher: University of Rostock
Francesca Cordero: University of Torino
Federica Di Nicolantonio: University of Torino
Alberto Bardelli: University of Torino

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8002

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