Gene expression of matched treatment-naive versus FOLFIRINOX-treated PDAC patient-derived organoids

In our study, we aimed to investigate adaptive processes of tumors under treatment and therefore, generated PDAC patient-derived organoids (PDOs) and 2D cell lines before and after chemotherapy. We enrolled a patient with borderline resectable PDAC who received neoadjuvant FOLFIRINOX. Endoscopic fine needle (pre-FFX) and surgical biopsies (post-FFX) were used to generate PDOs and 2D cells. Whole exome sequencing (WES) and RNA sequencing data of the pre-FFX and post-FFX organoids were compared in order to evaluate the genetic landscape and PDAC subtypes. Although transcriptional subtyping classified both PDOs as classical PDAC, gene set enrichment analysis (GSEA) revealed a reduced pathway activation linked to the basal-like phenotype such as KRAS signaling in the post-FFX organoids. WES did not show major differences in the genetic landscape of the tumor pre- and post-FFX induction suggesting a plasticity process rather than a clonal selection during chemotherapy. 2D cells were subjected to an unbiased automated drug screening of 415 compounds to investigate FFX-induced vulnerabilities. Top targets such as MEK inhibitors were validated manually in the 2D cells and organoids and an increased sensitivity was observed in the post-FFX cells. Thus, integrating functional layers into personalized medicine allows to identify chemotherapy-induced vulnerabilities as potent targeted therapy options in PDAC. Overall design: Bulk gene expression data are presented for matching treatment-naive and FOLFIRINOX-treated patient-derived organoids of pancreatic ductal adenocarcinoma.