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Open Access Highly Accessed Research article

Subtypes of primary colorectal tumors correlate with response to targeted treatment in colorectal cell lines

Andreas Schlicker1, Garry Beran3, Christine M Chresta3, Gael McWalter4, Alison Pritchard3, Susie Weston4, Sarah Runswick4, Sara Davenport3, Kerry Heathcote3, Denis Alferez Castro3, George Orphanides3, Tim French4* and Lodewyk FA Wessels125*

Author Affiliations

1 Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands

2 Faculty of EEMCS, Delft University of Technology, Delft, The Netherlands

3 Oncology iMed, AstraZeneca R&D, Alderley Park, Macclesfield, United Kingdom

4 Personalised Healthcare and Biomarkers Group, AstraZeneca R&D, Alderley Park, Macclesfield, United Kingdom

5 Department of Molecular Carcinogenesis, Plesmanlaan 121, Amsterdam, 1066CX, The Netherlands

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BMC Medical Genomics 2012, 5:66  doi:10.1186/1755-8794-5-66

Published: 31 December 2012

Abstract

Background

Colorectal cancer (CRC) is a heterogeneous and biologically poorly understood disease. To tailor CRC treatment, it is essential to first model this heterogeneity by defining subtypes of patients with homogeneous biological and clinical characteristics and second match these subtypes to cell lines for which extensive pharmacological data is available, thus linking targeted therapies to patients most likely to respond to treatment.

Methods

We applied a new unsupervised, iterative approach to stratify CRC tumor samples into subtypes based on genome-wide mRNA expression data. By applying this stratification to several CRC cell line panels and integrating pharmacological response data, we generated hypotheses regarding the targeted treatment of different subtypes.

Results

In agreement with earlier studies, the two dominant CRC subtypes are highly correlated with a gene expression signature of epithelial-mesenchymal-transition (EMT). Notably, further dividing these two subtypes using iNMF (iterative Non-negative Matrix Factorization) revealed five subtypes that exhibit activation of specific signaling pathways, and show significant differences in clinical and molecular characteristics. Importantly, we were able to validate the stratification on independent, published datasets comprising over 1600 samples. Application of this stratification to four CRC cell line panels comprising 74 different cell lines, showed that the tumor subtypes are well represented in available CRC cell line panels. Pharmacological response data for targeted inhibitors of SRC, WNT, GSK3b, aurora kinase, PI3 kinase, and mTOR, showed significant differences in sensitivity across cell lines assigned to different subtypes. Importantly, some of these differences in sensitivity were in concordance with high expression of the targets or activation of the corresponding pathways in primary tumor samples of the same subtype.

Conclusions

The stratification presented here is robust, captures important features of CRC, and offers valuable insight into functional differences between CRC subtypes. By matching the identified subtypes to cell line panels that have been pharmacologically characterized, it opens up new possibilities for the development and application of targeted therapies for defined CRC patient sub-populations.

Keywords:
Colorectal cancer; Tumor subtyping; Cell lines; Targeted therapy