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

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Moritz Schutte, 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 & 26 more 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, Marie-Laure Yaspo

Original languageEnglish
Article number14262
Pages (from-to)1-19
Number of pages19
JournalNature Communications
Volume8
DOIs
Published10 Feb 2017

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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.

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