title: Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors.
abstract: Colorectal carcinoma represents a heterogeneous entity, with only a fraction of the tumours responding to available therapies, requiring a better molecular understanding of the disease in precision oncology. To address this challenge, the OncoTrack consortium recruited 106 CRC patients (stages I-IV) and developed a pre-clinical platform generating a compendium of drug sensitivity data totalling >4,000 assays testing 16 clinical drugs on patient-derived in vivo and in vitro models. This large biobank of 106 tumours, 35 organoids and 59 xenografts, with extensive omics data comparing donor tumours and derived models provides a resource for advancing our understanding of CRC. Models recapitulate many of the genetic and transcriptomic features of the donors, but defined less complex molecular sub-groups because of the loss of human stroma. Linking molecular profiles with drug sensitivity patterns identifies novel biomarkers, including a signature outperforming RAS/RAF mutations in predicting sensitivity to the EGFR inhibitor cetuximab.
authors.affiliation: Alacris Theranostics GmbH, Fabeckstr. 60-62, D-14195 Berlin, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Schütte
authors.affiliation: Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics/Otto Warburg Laboratory Gene Regulation and Systems Biology of cancer, Ihnestrasse 73, D-14195 Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Risch
authors.affiliation: Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics/Otto Warburg Laboratory Gene Regulation and Systems Biology of cancer, Ihnestrasse 73, D-14195 Berlin, Germany.
authors.forename: Nilofar
authors.initials: N
authors.lastname: Abdavi-Azar
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Quantitative Biology, Avda. de la Industria 30, Alcobendas, 28108 Madrid, Spain.
authors.forename: Karsten
authors.initials: K
authors.lastname: Boehnke
authors.affiliation: Charité-Universitätsmedizin Berlin, Institute of Pathology, Laboratory for Molecular Tumour Pathology, Charitéplatz 1, 10117 Berlin, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69192 Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schumacher
authors.affiliation: Experimental Pharmacology and Oncology Berlin-Buch GmbH (EPO), Robert-Roessle-Str. 10, 13125 Berlin, Germany.
authors.forename: Marlen
authors.initials: M
authors.lastname: Keil
authors.affiliation: Alacris Theranostics GmbH, Fabeckstr. 60-62, D-14195 Berlin, Germany.
authors.forename: Reha
authors.initials: R
authors.lastname: Yildiriman
authors.affiliation: Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics/Otto Warburg Laboratory Gene Regulation and Systems Biology of cancer, Ihnestrasse 73, D-14195 Berlin, Germany.
authors.forename: Christine
authors.identifier: 0000-0003-1357-4401
authors.initials: C
authors.lastname: Jandrasits
authors.affiliation: Alacris Theranostics GmbH, Fabeckstr. 60-62, D-14195 Berlin, Germany.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Borodina
authors.affiliation: Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics/Otto Warburg Laboratory Gene Regulation and Systems Biology of cancer, Ihnestrasse 73, D-14195 Berlin, Germany.
authors.forename: Vyacheslav
authors.identifier: 0000-0002-1384-7599
authors.initials: V
authors.lastname: Amstislavskiy
authors.affiliation: Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics/Otto Warburg Laboratory Gene Regulation and Systems Biology of cancer, Ihnestrasse 73, D-14195 Berlin, Germany.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Worth
authors.affiliation: Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria.
authors.forename: Caroline
authors.initials: C
authors.lastname: Schweiger
authors.affiliation: Charité-Universitätsmedizin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Liebs
authors.affiliation: Bayer Pharma AG, Müllerstraße 178, 13353 Berlin, Germany.
authors.forename: Martin
authors.identifier: 0000-0002-4045-3915
authors.initials: M
authors.lastname: Lange
authors.affiliation: Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics/Otto Warburg Laboratory Gene Regulation and Systems Biology of cancer, Ihnestrasse 73, D-14195 Berlin, Germany.
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Warnatz
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.|Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: Lee M
authors.initials: LM
authors.lastname: Butcher
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: James E
authors.initials: JE
authors.lastname: Barrett
authors.affiliation: Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics/Otto Warburg Laboratory Gene Regulation and Systems Biology of cancer, Ihnestrasse 73, D-14195 Berlin, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Sultan
authors.affiliation: Alacris Theranostics GmbH, Fabeckstr. 60-62, D-14195 Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wierling
authors.affiliation: Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria.|Center for Biomarker Research in Medicine, Stiftingtalstrasse 5, 8010 Graz, Austria.
authors.forename: Nicole
authors.initials: N
authors.lastname: Golob-Schwarzl
authors.affiliation: Department of Pathology, Hospital Graz Süd-West, Göstinger Straße 22, 8020 Graz, Austria.
authors.forename: Sigurd
authors.initials: S
authors.lastname: Lax
authors.affiliation: Department of Surgery, Hospital Brothers of Charity Graz, Marschallgasse 12, 8020 Graz, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Uranitsch
authors.affiliation: Experimental Pharmacology and Oncology Berlin-Buch GmbH (EPO), Robert-Roessle-Str. 10, 13125 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Becker
authors.affiliation: Charité-Universitätsmedizin Berlin, Institute of Pathology, Laboratory for Molecular Tumour Pathology, Charitéplatz 1, 10117 Berlin, Germany.|CPO-Cellular Phenomics&Oncology, Berlin-Buch GmbH, Robert-Rössle-Str. 10, 13125 Berlin, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Welte
authors.affiliation: Bayer Pharma AG, Müllerstraße 178, 13353 Berlin, Germany.
authors.forename: Joseph Lewis
authors.initials: JL
authors.lastname: Regan
authors.affiliation: Charité-Universitätsmedizin Berlin, Institute of Pathology, Laboratory for Molecular Tumour Pathology, Charitéplatz 1, 10117 Berlin, Germany.|CPO-Cellular Phenomics&Oncology, Berlin-Buch GmbH, Robert-Rössle-Str. 10, 13125 Berlin, Germany.
authors.forename: Maxine
authors.initials: M
authors.lastname: Silvestrov
authors.affiliation: Charité-Universitätsmedizin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Inge
authors.initials: I
authors.lastname: Kehler
authors.affiliation: Charité-Universitätsmedizin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Alberto
authors.initials: A
authors.lastname: Fusi
authors.affiliation: Alacris Theranostics GmbH, Fabeckstr. 60-62, D-14195 Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kessler
authors.affiliation: Max Planck Institute for Molecular Genetics, Department of Computational Molecular Biology, Ihnestrasse 73, D-14195 Berlin, Germany.
authors.forename: Ralf
authors.identifier: 0000-0002-9335-1760
authors.initials: R
authors.lastname: Herwig
authors.affiliation: Department of Immunology, Genetics and Pathology, SciLifeLab, Uppsala University, Box 815, SE-751 08 Uppsala, Sweden.
authors.forename: Ulf
authors.identifier: 0000-0002-7820-1000
authors.initials: U
authors.lastname: Landegren
authors.affiliation: Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Wienke
authors.affiliation: Department of Immunology, Genetics and Pathology, SciLifeLab, Uppsala University, Box 815, SE-751 08 Uppsala, Sweden.|Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Tomtebodavägem 23A, 17165 Solna, Stockholm, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Nilsson
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Quantitative Biology, Avda. de la Industria 30, Alcobendas, 28108 Madrid, Spain.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Velasco
authors.affiliation: Boehringer Ingelheim RCV GmbH &Co KG, Dr. Boehringer-Gasse 5-11, A-1121 Wien, Austria.
authors.forename: Pilar
authors.initials: P
authors.lastname: Garin-Chesa
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Oncology Translational Research, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Reinhard
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Stephan
authors.identifier: 0000-0001-5290-2151
authors.initials: S
authors.lastname: Beck
authors.affiliation: Charité-Universitätsmedizin Berlin, Institute of Pathology, Laboratory for Molecular Tumour Pathology, Charitéplatz 1, 10117 Berlin, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69192 Heidelberg, Germany.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schäfer
authors.affiliation: Charité-Universitätsmedizin Berlin, Institute of Pathology, Laboratory for Molecular Tumour Pathology, Charitéplatz 1, 10117 Berlin, Germany.|CPO-Cellular Phenomics&Oncology, Berlin-Buch GmbH, Robert-Rössle-Str. 10, 13125 Berlin, Germany.
authors.forename: Christian R A
authors.initials: CR
authors.lastname: Regenbrecht
authors.affiliation: Bayer Pharma AG, Global External Innovation &Alliances, Müllerstraße 178, 13353 Berlin, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Henderson
authors.affiliation: Alacris Theranostics GmbH, Fabeckstr. 60-62, D-14195 Berlin, Germany.
authors.forename: Bodo
authors.initials: B
authors.lastname: Lange
authors.affiliation: Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria.|Center for Biomarker Research in Medicine, Stiftingtalstrasse 5, 8010 Graz, Austria.
authors.forename: Johannes
authors.identifier: 0000-0001-5518-3359
authors.initials: J
authors.lastname: Haybaeck
authors.affiliation: Charité-Universitätsmedizin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Ulrich
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authors.affiliation: Experimental Pharmacology and Oncology Berlin-Buch GmbH (EPO), Robert-Roessle-Str. 10, 13125 Berlin, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Hoffmann
authors.affiliation: Alacris Theranostics GmbH, Fabeckstr. 60-62, D-14195 Berlin, Germany.|Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics/Otto Warburg Laboratory Gene Regulation and Systems Biology of cancer, Ihnestrasse 73, D-14195 Berlin, Germany.|Dahlem Centre for Genome Research and Medical Systems Biology, Fabeckstr. 60-62, 14195 Berlin, Germany.
authors.forename: Hans
authors.initials: H
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authors.affiliation: Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics/Otto Warburg Laboratory Gene Regulation and Systems Biology of cancer, Ihnestrasse 73, D-14195 Berlin, Germany.
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authors.identifier: 0000-0002-9555-9979
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mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D000068818:Cetuximab / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008875:Middle Aged; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D000074322:Antineoplastic Agents, Immunological; D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D000068818:Cetuximab