Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies

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http://hdl.handle.net/10138/234325

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Sveen , A , Bruun , J , Eide , P W , Eilertsen , I A , Ramirez , L , Murumägi , A , Arjama , M , Danielsen , S A , Kryeziu , K , Elez , E , Tabernero , J , Guinney , J , Palmer , H G , Nesbakken , A , Kallioniemi , O , Dienstmann , R & Lothe , R A 2018 , ' Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies ' , Clinical Cancer Research , vol. 24 , no. 4 , pp. 794-806 . https://doi.org/10.1158/1078-0432.CCR-17-1234

Title: Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies
Author: Sveen, Anita; Bruun, Jarle; Eide, Peter W.; Eilertsen, Ina A.; Ramirez, Lorena; Murumägi, Astrid; Arjama, Mariliina; Danielsen, Stine A.; Kryeziu, Kushtrim; Elez, Elena; Tabernero, Josep; Guinney, Justin; Palmer, Hector G.; Nesbakken, Arild; Kallioniemi, Olli; Dienstmann, Rodrigo; Lothe, Ragnhild A.
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Olli-Pekka Kallioniemi / Principal Investigator
Date: 2018-02-15
Language: eng
Number of pages: 13
Belongs to series: Clinical Cancer Research
ISSN: 1078-0432
URI: http://hdl.handle.net/10138/234325
Abstract: Purpose: Response to standard oncologic treatment is limited in colorectal cancer. The gene expression-based consensus molecular subtypes (CMS) provide a new paradigm for stratified treatment and drug repurposing; however, drug discovery is currently limited by the lack of translation of CMS to preclinical models. Experimental Design: We analyzed CMS in primary colorectal cancers, cell lines, and patient-derived xenografts (PDX). For classification of preclinical models, we developed an optimized classifier enriched for cancer cell-intrinsic gene expression signals, and performed high-throughput in vitro drug screening (n = 459 drugs) to analyze subtype-specific drug sensitivities. Results: The distinct molecular and clinicopathologic characteristics of each CMS group were validated in a single-hospital series of 409 primary colorectal cancers. The new, cancer cell-adapted classifier was found to perform well in primary tumors, and applied to a panel of 148 cell lines and 32 PDXs, these colorectal cancer models were shown to recapitulate the biology of the CMS groups. Drug screening of 33 cell lines demonstrated subtype-dependent response profiles, confirming strong response to EGFR and HER2 inhibitors in the CMS2 epithelial/canonical group, and revealing strong sensitivity to HSP90 inhibitors in cells with the CMS1 microsatellite instability/immune and CMS4 mesenchymal phenotypes. This association was validated in vitro in additional CMS-predicted cell lines. Combination treatment with 5-fluorouracil and luminespib showed potential to alleviate chemoresistance in a CMS4 PDX model, an effect not seen in a chemosensitive CMS2 PDX model. Conclusions: We provide translation of CMS classification to preclinical models and uncover a potential for targeted treatment repurposing in the chemoresistant CMS4 group. (C) 2017 AACR.
Subject: COLON-CANCER
MICROSATELLITE INSTABILITY
HETEROGENEITY
LINES
THERAPY
PROGNOSIS
PATTERNS
CLASSIFICATION
SENSITIVITY
INHIBITORS
3122 Cancers
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