Journal Article

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

Schumacher, Dirk, Liebs, Sandra, Barrett, James E., Regan, Joseph Lewis, Uranitsch, Stefan, Garin-Chesa, Pilar, Schäfer, Reinhold, Lange, Bodo, Jandrasits, Christine, Sultan, Marc, Regenbrecht, Christian R. A., Silvestrov, Maxine, Henderson, David, Yildiriman, Reha, Lehrach, Hans, Herwig, Ralf, Schütte, Moritz, Beck, Stephan, Kehler, Inge, Golob-Schwarzl, Nicole, Abdavi-Azar, Nilofar, Lange, Martin, Keil, Marlen, Butcher, Lee M., Haybaeck, Johannes, Welte, Yvonne, Fusi, Alberto, Nilsson, Mats, Keilholz, Ulrich, Borodina, Tatiana, Schweiger, Caroline, Wierling, Christoph, Velasco, Juan A., Boehnke, Karsten, Worth, Catherine L., Yaspo, Marie-Laure, Warnatz, Hans- Jörg, Lax, Sigurd, Reinhard, Christoph, Kessler, Thomas, Amstislavskiy, Vyacheslav, Landegren, Ulf, Hoffmann, Jens, Risch, Thomas, Becker, Michael, Wienke, Dirk

2017

Overview

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. The heterogeneity of colorectal cancer has important clinical and therapeutic implications. Here the authors analysed the responses of a large biobank of organoids and xenografts derived from colorectal patients to a panel of clinically relevant therapeutic agents to identify genes signatures associated with drug response.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 38 / 631/154/309/436/2388 / 64 / 64/60 / 692/53/2423 / 692/699/67/1504/1885 / 692/699/67/70 / Adolescent / Adult / Aged / Aged, 80 and over / Animals / Antineoplastic Agents, Immunological - therapeutic use / Biobanks / Biomarkers / Biomarkers, Tumor - genetics / Biomarkers, Tumor - metabolism / Cetuximab - therapeutic use / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - genetics / Colorectal Neoplasms - metabolism / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / Humanities and Social Sciences / Humans / Kinases / Mice / Middle Aged / multidisciplinary / Mutation / Patients / Receptor, Epidermal Growth Factor - antagonists & inhibitors / Receptor, Epidermal Growth Factor - metabolism / Science / Science (multidisciplinary) / Tumors / Xenograft Model Antitumor Assays / Young Adult