Examining FOLFIRINOX Resistance in Pancreatic Cancer through the Creation of Resistant Cell Culture Models

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive form of cancer with a 5-year survival rate of 8.5%. PDAC is often characterized by its early-stage metastasis, resistance to cytotoxic chemotherapy, and extremely poor prognosis. A leading treatment for patients who can tolerate its severe side effects is a cocktail of 4 chemotherapeutic drugs, leucovorin, 5-fluorouricil, irinotecan, and oxaliplatin (FOLFIRINOX). Despite FOLFIRINOX being a leading treatment for patients with pancreatic cancer, the cellular response to the treatment is poorly understood. This investigation focused on chemotherapy resistance to FOLFIRINOX in four PDAC cell lines. To determine initial sensitivity to the drug cocktail, PDAC cells were dosed with FOLFIRINOX at a ratio similar to that used clinically. Cell viability was assessed to calculate GI50­ concentrations. The PANC 03.27 cell line was found to be the most sensitive to FOLFIRINOX with a GI50 concentration of 0.71 mM, while PANC 04.03 was found to have a GI50 value of 1.33 mM. These two cell lines were then cultured in FOLFIRINOX to create a clinically relevant model of chemotherapy resistance. To assess resistance, post-treatment GI­50­ assays were performed and demonstrated a 1.6-fold increase in FOLFIRINOX resistance in PANC 03.27 cells. Additionally, RNA Sequencing was performed on untreated control, DMSO control, and FOLFIRINOX-treated cells to identify changes in the transcriptome and possible mechanisms promoting chemotherapy resistance. Changes in gene expression accompanying resistance may lend insight into the underlying mechanism of resistance in FOLFIRINOX experienced by many patients with pancreatic cancer.