Abstract Recently, unsupervised gene expression-based signatures with prognostic and potential predictive implications were proposed for colorectal cancer (CRC) classification. The challenge is now to characterize the genomic alterations of CRC subtypes and their sensitivity to therapies. Patient derived xenograft models (PDX) may be a valuable tool for this purpose, as they retain the molecular features and drug response patterns of their parental patient tumors. In this study, we classified our collection of colon PDX into transcriptomic subtypes and investigated the associations with genomic alterations and in vivo responses to cetuximab (CTX), oxaliplatin (OXT) and irinotecan (IR). We determined expression profiles of 67 PDX models using Affymetrix HGU133 Plus2.0 arrays and applied the CRC assigner-786 gene expression signature reported by Sadanandam et al. to classify our PDX into 5 subtypes. We identified 34 (51%) transit-amplifying (TA), 15 (22%) goblet-like (GL), 10 (15%) inflammatory (IF), 7 (10%) enterocyte (ET) and 1 (1%) stem-like (SL) PDX models. TA showed a gene signature of WNT pathway activation whereas GL, ET and IF PDX subtypes harbored gene signatures of KRAS pathway activation. As analyzed by whole exome sequencing and Affymetrix SNP6.0 array, the GL, ET and IF subtypes were found to display different signatures of mutational processes, mutations and chromosomal rearrangement patterns than TA and SL. Of particular note, mutations in BRAF, PIK3CA/PTEN, TGFBR2/SMAD4 or NOTCH1 were mainly found in GL, ET or IF while mutations in APC, TP53 and KRAS were not associated with a given subtype. Regarding PDX drug sensitivity, 10/11 TA/SL PDX with unaltered KRAS/PIK3CA/PTEN/HER2 status were sensitive to CTX whereas 9/12 models with alterations were resistant. TA and SL PDX were also frequently sensitive to IR and OXT (6/10 and 4/10, respectively). In the IF subtype, 6/6 PDX showing KRAS, PIK3CA or PTEN alterations were resistant to CTX. Of interest, 5/5 IF PDX were sensitive to IR treatment. As in IF PDX, GL and ET often had alterations in KRAS/PIK3CA/PTEN/HER2 and were resistant to CTX. Moreover, these subtypes were resistant to both IR and OXT. Furthermore, the frequent KRAS pathway activation and the presence of actionable mutations in GL, ET and IF would advocate the testing of inhibitors (as monotherapy or in combination) of BRAF, PI3K or MEK in tumors of these subtypes while WNT inhibitors should be tested in TA models.Molecular classification of our colon PDX collection confirmed their similarities with patient tumors. Investigation of drug sensitivity resulted in the identification of PDX subtypes which respond poorly to standard therapies and which require different treatment options. Testing alternative and combined therapies in PDX may be a valuable approach to optimize personalized medicine. Citation Format: Anne-Lise Peille, Christina Gredy, Bruno Zeitouni, Armin Maier, Kerstin Klingner, Tim Kees, Julia Schüler, Thomas Metz, Heinz. Herbert Fiebig, Vincent Vuaroqueaux. Classification of colorectal PDX into transcriptomic subtypes associated with distinct genomic alteration profiles and in vivo response patterns to therapies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1705. doi:10.1158/1538-7445.AM2015-1705