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

• Published in: Nature communications Vol. 8; no. 1; p. 14262
• Main Authors: Schütte, Moritz, Risch, Thomas, Abdavi-Azar, Nilofar, Boehnke, Karsten, Schumacher, Dirk, Keil, Marlen, Yildiriman, Reha, Jandrasits, Christine, Borodina, Tatiana, Amstislavskiy, Vyacheslav, Worth, Catherine L., Schweiger, Caroline, Liebs, Sandra, Lange, Martin, Warnatz, Hans- Jörg, Butcher, Lee M., Barrett, James E., Sultan, Marc, Wierling, Christoph, Golob-Schwarzl, Nicole, Lax, Sigurd, Uranitsch, Stefan, Becker, Michael, Welte, Yvonne, Regan, Joseph Lewis, Silvestrov, Maxine, Kehler, Inge, Fusi, Alberto, Kessler, Thomas, Herwig, Ralf, Landegren, Ulf, Wienke, Dirk, Nilsson, Mats, Velasco, Juan A., Garin-Chesa, Pilar, Reinhard, Christoph, Beck, Stephan, Schäfer, Reinhold, Regenbrecht, Christian R. A., Henderson, David, Lange, Bodo, Haybaeck, Johannes, Keilholz, Ulrich, Hoffmann, Jens, Lehrach, Hans, Yaspo, Marie-Laure
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10-02-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 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 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
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14262

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.