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

被引：243

作者：

Schuette, Moritz ^{[1
]}

Risch, Thomas ^{[2
]}

Abdavi-Azar, Nilofar ^{[2
]}

Boehnke, Karsten ^{[3
]}

Schumacher, Dirk ^{[4
,5
]}

Keil, Marlen ^{[6
]}

Yildirimman, Reha ^{[1
]}

Jandrasits, Christine ^{[2
]}

Borodina, Tatiana ^{[1
]}

Amstislavskiy, Vyacheslav ^{[2
]}

Worth, Catherine L. ^{[2
]}

Schweiger, Caroline ^{[7
]}

Liebs, Sandra ^{[8
]}

Lange, Martin ^{[9
]}

Warnatz, Hans-Joerg ^{[2
]}

Butcher, Lee M. ^{[10
,11
]}

Barrett, James E. ^{[10
]}

Sultan, Marc ^{[2
]}

Wierling, Christoph ^{[1
]}

Golob-Schwarzl, Nicole ^{[12
]}

Lax, Sigurd ^{[13
]}

Uranitsch, Stefan ^{[14
]}

Becker, Michael ^{[6
]}

Welte, Yvonne ^{[4
,15
]}

Regan, Joseph Lewis ^{[9
]}

Silvestrov, Maxine ^{[4
,15
]}

Kehler, Inge ^{[8
]}

Fusi, Alberto ^{[8
]}

Kessler, Thomas ^{[1
]}

Herwig, Ralf ^{[16
]}

Landegren, Ulf ^{[17
]}

Wienke, Dirk ^{[18
]}

Nilsson, Mats ^{[17
,19
]}

Velasco, Juan A. ^{[3
]}

Garin-Chesa, Pilar ^{[20
]}

Reinhard, Christoph ^{[21
]}

Beck, Stephan ^{[10
]}

Schaefer, Reinhold ^{[4
,5
]}

Regenbrecht, Christian R. A. ^{[4
,15
]}

Henderson, David ^{[22
]}

Lange, Bodo ^{[1
]}

Haybaeck, Johannes ^{[7
,12
]}

Keilholz, Ulrich ^{[8
]}

Hoffmann, Jens ^{[6
]}

Lehrach, Hans ^{[1
,2
,23
]}

Yaspo, Marie-Laure ^{[2
]}

机构：

[1] Alacris Theranost GmbH, Fabeckstr 60-62, D-14195 Berlin, Germany

[2] Max Planck Inst Mol Genet, Dept Vertebrate Genom, Otto Warburg Lab Gene Regulat & Syst Biol Canc, Ihnestr 73, D-14195 Berlin, Germany

[3] Eli Lilly & Co, Lilly Res Labs, Quantitat Biol, Avda Ind 30, Madrid 28108, Spain

[4] Charite Univ Med Berlin, Inst Pathol, Lab Mol Tumour Pathol, Charitepl 1, D-10117 Berlin, Germany

[5] German Canc Res Ctr, German Canc Consortium DKTK, Neuenheimer Feld 280, D-69192 Heidelberg, Germany

[6] Expt Pharmacol & Oncol Berlin Buch GmbH EPO, Robert Roessle Str 10, D-13125 Berlin, Germany

[7] Med Univ Graz, Inst Pathol, Auenbruggerpl 25, A-8036 Graz, Austria

[8] Charite, Charitepl 1, D-10117 Berlin, Germany

[9] Bayer Pharma AG, Mullerstr 178, D-13353 Berlin, Germany

[10] UCL, Inst Canc, London WC1E 6BT, England

[11] Imperial Coll London, Dept Surg & Canc, London W12 0NN, England

[12] Ctr Biomarker Res Med, Stiftingtalstr 5, A-8010 Graz, Austria

[13] Hosp Graz Sud West, Dept Pathol, Gostinger Str 22, A-8020 Graz, Austria

[14] Hosp Bros Char Graz, Dept Surg, Marschallgasse 12, A-8020 Graz, Austria

[15] Berlin Buch GmbH, CPO Cellular Phenom & Oncol, Robert Rossle Str 10, D-13125 Berlin, Germany

[16] Max Planck Inst Mol Genet, Dept Computat Mol Biol, Ihnestr 73, D-14195 Berlin, Germany

[17] Uppsala Univ, Dept Immunol Genet & Pathol, SciLifeLab, Box 815, SE-75108 Uppsala, Sweden

[18] Merck KGaA, Frankfurter Str 250, D-64293 Darmstadt, Germany

[19] Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Tomtebodavagem 23A, S-17165 Stockholm, Sweden

[20] Boehringer Ingelheim RCV GmbH & Co KG, Dr Boehringer Gasse 5-11, A-1121 Vienna, Austria

[21] Eli Lilly & Co, Lilly Res Labs, Lilly Corp Ctr, Oncol Translat Res, Indianapolis, IN 46285 USA

[22] Bayer Pharma AG, Global External Innovat & Alliances, Mullerstr 178, D-13353 Berlin, Germany

[23] Dahlem Ctr Genome Res & Med Syst Biol, Fabeckstr 60-62, D-14195 Berlin, Germany

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

基金：

瑞典研究理事会;

关键词：

BRAF MUTATION STATUS; ANTITUMOR-ACTIVITY; COLON-CANCER; 1ST-LINE TREATMENT; DNA METHYLATION; GENE-EXPRESSION; TUMOR-GROWTH; CELL-LINES; CETUXIMAB; LANDSCAPE;

D O I：

10.1038/ncomms14262

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 44,000 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.

引用

页数：19

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