Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors

Moritz Schütte, Thomas Risch, Nilofar Abdavi-Azar, Karsten Boehnke, Dirk Schumacher, Marlen Keil, Reha Yildiriman, Christine Jandrasits, Tatiana Borodina, Vyacheslav Amstislavskiy, Catherine L. Worth, Caroline Schweiger, Sandra Liebs, Martin Lange, Hans- Jörg Warnatz, Lee M. Butcher, James E. Barrett, Marc Sultan, Christoph Wierling, Nicole Golob-Schwarzl, Sigurd Lax, Stefan Uranitsch, Michael Becker, Yvonne Welte, Joseph Lewis Regan, Maxine Silvestrov, Inge Kehler, Alberto Fusi, Thomas Kessler, Ralf Herwig, Ulf Landegren, Dirk Wienke, Mats Nilsson, Juan A. Velasco, Pilar Garin-Chesa, Christoph Reinhard, Stephan Beck, Reinhold Schäfer, Christian R. A. Regenbrecht, David Henderson (), Bodo Lange, Johannes Haybaeck, Ulrich Keilholz, Jens Hoffmann, Hans Lehrach () and Marie-Laure Yaspo ()
Additional contact information
Moritz Schütte: Alacris Theranostics GmbH
Thomas Risch: Max Planck Institute for Molecular Genetics
Nilofar Abdavi-Azar: Max Planck Institute for Molecular Genetics
Karsten Boehnke: Eli Lilly and Company, Lilly Research Laboratories, Quantitative Biology
Dirk Schumacher: Charité–Universitätsmedizin Berlin, Institute of Pathology, Laboratory for Molecular Tumour Pathology
Marlen Keil: Experimental Pharmacology and Oncology Berlin-Buch GmbH (EPO)
Reha Yildiriman: Alacris Theranostics GmbH
Christine Jandrasits: Max Planck Institute for Molecular Genetics
Tatiana Borodina: Alacris Theranostics GmbH
Vyacheslav Amstislavskiy: Max Planck Institute for Molecular Genetics
Catherine L. Worth: Max Planck Institute for Molecular Genetics
Caroline Schweiger: Institute of Pathology, Medical University of Graz
Sandra Liebs: Charité-Universitätsmedizin, Charitéplatz 1
Martin Lange: Bayer Pharma AG, Müllerstraße 178
Hans- Jörg Warnatz: Max Planck Institute for Molecular Genetics
Lee M. Butcher: UCL Cancer Institute, University College London
James E. Barrett: UCL Cancer Institute, University College London
Marc Sultan: Max Planck Institute for Molecular Genetics
Christoph Wierling: Alacris Theranostics GmbH
Nicole Golob-Schwarzl: Institute of Pathology, Medical University of Graz
Sigurd Lax: Hospital Graz Süd-West
Stefan Uranitsch: Hospital Brothers of Charity Graz
Michael Becker: Experimental Pharmacology and Oncology Berlin-Buch GmbH (EPO)
Yvonne Welte: Charité–Universitätsmedizin Berlin, Institute of Pathology, Laboratory for Molecular Tumour Pathology
Joseph Lewis Regan: Bayer Pharma AG, Müllerstraße 178
Maxine Silvestrov: Charité–Universitätsmedizin Berlin, Institute of Pathology, Laboratory for Molecular Tumour Pathology
Inge Kehler: Charité-Universitätsmedizin, Charitéplatz 1
Alberto Fusi: Charité-Universitätsmedizin, Charitéplatz 1
Thomas Kessler: Alacris Theranostics GmbH
Ralf Herwig: Max Planck Institute for Molecular Genetics
Ulf Landegren: Genetics and Pathology, SciLifeLab, Uppsala University
Dirk Wienke: Merck KGaA
Mats Nilsson: Genetics and Pathology, SciLifeLab, Uppsala University
Juan A. Velasco: Eli Lilly and Company, Lilly Research Laboratories, Quantitative Biology
Pilar Garin-Chesa: Boehringer Ingelheim RCV GmbH & Co KG
Christoph Reinhard: Eli Lilly and Company, Lilly Research Laboratories, Oncology Translational Research, Lilly Corporate Center
Stephan Beck: UCL Cancer Institute, University College London
Reinhold Schäfer: Charité–Universitätsmedizin Berlin, Institute of Pathology, Laboratory for Molecular Tumour Pathology
Christian R. A. Regenbrecht: Charité–Universitätsmedizin Berlin, Institute of Pathology, Laboratory for Molecular Tumour Pathology
David Henderson: Bayer Pharma AG, Global External Innovation & Alliances
Bodo Lange: Alacris Theranostics GmbH
Johannes Haybaeck: Institute of Pathology, Medical University of Graz
Ulrich Keilholz: Charité-Universitätsmedizin, Charitéplatz 1
Jens Hoffmann: Experimental Pharmacology and Oncology Berlin-Buch GmbH (EPO)
Hans Lehrach: Alacris Theranostics GmbH
Marie-Laure Yaspo: Max Planck Institute for Molecular Genetics

Nature Communications, 2017, vol. 8, issue 1, 1-19

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14262

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