title: Subtypes of primary colorectal tumors correlate with response to targeted treatment in colorectal cell lines.
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.
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlicker
authors.forename: Garry
authors.initials: G
authors.lastname: Beran
authors.forename: Christine M
authors.initials: CM
authors.lastname: Chresta
authors.forename: Gael
authors.initials: G
authors.lastname: McWalter
authors.forename: Alison
authors.initials: A
authors.lastname: Pritchard
authors.forename: Susie
authors.initials: S
authors.lastname: Weston
authors.forename: Sarah
authors.initials: S
authors.lastname: Runswick
authors.forename: Sara
authors.initials: S
authors.lastname: Davenport
authors.forename: Kerry
authors.initials: K
authors.lastname: Heathcote
authors.forename: Denis Alferez
authors.initials: DA
authors.lastname: Castro
authors.forename: George
authors.initials: G
authors.lastname: Orphanides
authors.forename: Tim
authors.initials: T
authors.lastname: French
authors.forename: Lodewyk F A
authors.initials: LF
authors.lastname: Wessels
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000145:classification* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D030541:Databases, Genetic; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors