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 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.
1] Department of Oncology, University of Torino, SP 142, Km 3.95, 10060, Candiolo, Torino, Italy [2] Candiolo Cancer Institute-FPO, IRCCS, 10060, Candiolo (TO), Italy.
Enzo
E
Medico
1] Department of Oncology, University of Torino, SP 142, Km 3.95, 10060, Candiolo, Torino, Italy [2] Candiolo Cancer Institute-FPO, IRCCS, 10060, Candiolo (TO), Italy [3] FIRC Institute of Molecular Oncology (IFOM), 20139 Milano, Italy.
Mariangela
M
Russo
1] Department of Oncology, University of Torino, SP 142, Km 3.95, 10060, Candiolo, Torino, Italy [2] Candiolo Cancer Institute-FPO, IRCCS, 10060, Candiolo (TO), Italy.
Gabriele
G
Picco
Candiolo Cancer Institute-FPO, IRCCS, 10060, Candiolo (TO), Italy.
Carlotta
C
Cancelliere
Department of Hematology and Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.
Emanuele
E
Valtorta
Candiolo Cancer Institute-FPO, IRCCS, 10060, Candiolo (TO), Italy.
Giorgio
0000000163794117
G
Corti
Candiolo Cancer Institute-FPO, IRCCS, 10060, Candiolo (TO), Italy.
Michela
M
Buscarino
Department of Oncology, University of Torino, SP 142, Km 3.95, 10060, Candiolo, Torino, Italy.
Claudio
C
Isella
1] Department of Oncology, University of Torino, SP 142, Km 3.95, 10060, Candiolo, Torino, Italy [2] Candiolo Cancer Institute-FPO, IRCCS, 10060, Candiolo (TO), Italy.
Simona
S
Lamba
Candiolo Cancer Institute-FPO, IRCCS, 10060, Candiolo (TO), Italy.
Barbara
B
Martinoglio
Department of Hematology and Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.
Silvio
S
Veronese
Department of Hematology and Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.
Salvatore
S
Siena
Department of Hematology and Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.
Andrea
A
Sartore-Bianchi
Department of Computer Science, University of Torino, 10149 Torino, Italy.
Marco
M
Beccuti
S.C. Anatomia Patologica, Istituto Nazionale Tumori Regina Elena, 00144 Roma, Italy.
Marcella
M
Mottolese
Division of Molecular Oncology and Immunotherapy, University of Rostock, D-18057 Rostock, Germany.
Michael
M
Linnebacher
Department of Computer Science, University of Torino, 10149 Torino, Italy.
Francesca
F
Cordero
1] Department of Oncology, University of Torino, SP 142, Km 3.95, 10060, Candiolo, Torino, Italy [2] Candiolo Cancer Institute-FPO, IRCCS, 10060, Candiolo (TO), Italy.
Federica
0000000196182010
F
Di Nicolantonio
1] Department of Oncology, University of Torino, SP 142, Km 3.95, 10060, Candiolo, Torino, Italy [2] Candiolo Cancer Institute-FPO, IRCCS, 10060, Candiolo (TO), Italy.
Alberto
A
Bardelli
D000077548:Anaplastic Lymphoma Kinase; D045744:Cell Line, Tumor; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D018773:Genes, erbB-1; D018740:Genetic Heterogeneity; D006801:Humans; D058990:Molecular Targeted Therapy; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism
C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; C496353:FGFR2 protein, human; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2; D000068818:Cetuximab