Organoids derived from neoadjuvant FOLFIRINOX patients recapitulate therapy resistance in pancreatic ductal adenocarcinoma

Abstract

Purpose: We investigated whether organoids can be generated display resistance to FOLFIRINOX (5/5), irinotecan (5/5), and from resected tumors of patients who received eight cycles of oxaliplatin (4/5) when compared with treatment-naïve organoids neoadjuvant FOLFIRINOX chemotherapy before surgery, and (FOLFIRINOX: 1/5, irinotecan: 2/5, oxaliplatin: 0/5). 5-Fluoroura-evaluated the sensitivity/resistance of these surviving cancer cells cil treatment responses between naïve and treated organoids were to cancer therapy. similar. Comparative global transcriptome analysis of treatment-Experimental Design: We generated a library of 10 pancreatic naïve and FOLFIRINOX samples—in both organoids and correductal adenocarcinoma (PDAC) organoid lines: five each from sponding matched tumor tissues—uncovered modulated pathways treatment-naïve and FOLFIRINOX-treated patients. We first mainly involved in genomic instability, energy metabolism, and assessed the histologic, genetic, and transcriptional characteristics innate immune system. of the organoids and their matched primary PDAC tissue. Next, the Conclusions: Resistance development in neoadjuvant FOL-organoids’ response to treatment with single agents—5-FU, irinoFIRINOX organoids, recapitulating their primary tumor resistecan, and oxaliplatin—of the FOLFIRINOX regimen as well as tance, suggests continuation of FOLFIRINOX therapy as an combined regimen was evaluated. Finally, global mRNA-seq anal-adjuvant treatment may not be advantageous for these patients. yses were performed to identify FOLFIRINOX resistance pathways. Gene-expression profiles of PDAC organoids identify targetable Results: All 10 patient-derived PDAC organoids recapitulate pathways involved in chemoresistance development upon histologic, genetic, and transcriptional characteristics of their prineoadjuvant FOLFIRINOX treatment, thus opening up combimary tumor tissue. Neoadjuvant FOLFIRINOX-treated organoids nation therapy possibilities.