Examining FOLFIRINOX resistance in pancreatic cancer through creating resistant cell culture models.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is extremely aggressive, often characterized by its early stage metastasis, resistance to cytotoxic chemotherapy, and extremely poor prognosis. FOLFIRINOX is the current standard of care for patients who can tolerate its side effects, and is a cocktail of four anti-cancer drugs: 5-fluorouricil, leucovorin, oxaliplatin, and irinotecan. This investigation focuses on chemotherapy resistance to FOLFIRINOX in multiple PDAC cell lines. Using dosages based on ratios of each drug given clinically, GI50 assays with a cocktail of all 4 anti-cancer drugs in FOLFIRINOX were conducted in four independent PDAC cell lines. Initial measurements for relative sensitivity based on the concentration of drug cocktail needed to inhibit the growth of 50% of the population, the PANC 03.27 cell line was found to be the most sensitive to FOLFIRINOX with a GI50 value of 0.71 mM, while PANC 05.04 was found to be the most resistant with a GI50 value of 1.50 mM. These two cell lines were chosen to then be cultured in FOLFIRINOX in order to create a model of chemotherapy resistance. Both PDAC lines were treated with their GI10 dosage for 3 days and then allowed to grow until confluent. This treatment process was repeated multiple times with the goal of building and maintaining resistance to FOLFIRINOX. Currently, both cell lines have undergone three FOLFIRINOX treatments, and GI50 assays are being run to identify their change in resistance. After resistance is achieved, RNA sequencing will be performed on both treated (resistant) and untreated cells. Changes in gene expression accompanying resistance may lend insight into the underlining mechanism of resistance in FOLFIRINOX experienced by many patients with pancreatic cancer.