194 Pancreatic ductal organoids as a new platform for drug discovery

Abstract

stroma content and vascularization. At the transcriptomic level, we identified several PDX clusters similar to Goblet-like, Enterocyte, Transit-Amplifying, Inflammatory and Stem-like subtypes recently reported in CRC patients. In addition, well and moderately differentiated PDX showed a different gene expression profile than poorly and undifferentiated models. At the genomic level, the colon PDX models exhibited alteration profiles comparable to those reported for patient tumors regarding signatures of mutational processes (patient-age related or associated to mismatch repair gene deficiencies), chromosomal rearrangement and mutated genes (e.g. APC, TP53, KRAS and TP53). Moreover, we identified 6 PDX models with microsatellite instability (MSI), 5 of them being hyper-mutant with a loss of MLH1 expression. Interestingly, colon PDX displaying the MSI phenotype showed gene expression patterns of the Globlet-like or Inflammatory subtypes. To demonstrate the potential of our approach, we searched for molecular determinants of cetuximab sensitivity in colon PDX by combining in vivo drug sensitivity and molecular data. The study identified the Transit Amplifying subtype, AREG/EREG expression and KRAS mutation among the best predictors of response. Similarly, predictive biomarkers for oxaliplatin and irinotecan were found, and their associations with particular PDX subtypes are under investigation. The accuracy in predicting patient outcome following treatment with FOLFOX and FOLFIRI will be evaluated by assessing publicly available datasets. The comprehensive characterization of our colon PDX models confirmed their similarities with patient tumors and their inter-tumoral diversity. The combined use of PDX molecular and drug sensitivity data represents a promising approach for biomarker identification and tumor response prediction at a preclinical stage.