Pharmacologic ascorbate resistant pancreatic cancer demonstrates enhanced metastatic potential

Pharmacological ascorbate (P-AscH, high-dose, intravenous, vitamin C), is a pro-drug that generates hydrogen peroxide (H₂O₂) and is being investigated as a neoadjuvant treatment for pancreatic adenocarcinoma (PDAC). In a randomized, phase II clinical trial, P-AscH demonstrated encouraging results in terms of efficacy and safety. However, some patients do not respond to P-AscH suggesting that resistance occurs in a subset of patients. The aims of this study were two-fold: first to characterize PDAC cells resistant to P-AscH, and second, determine if these alterations enhance metastatic potential. Resistance to P-AscH increased the ability to detoxify H₂O₂, altered redox metabolism and cell cycle regulation, however mechanisms to P-AscH resistance were different in the cell lines studied. Transcriptomic analysis demonstrated a significant enrichment of the epithelial-to-mesenchymal gene expression pattern in the cell lines studied, suggesting that upregulation of metastatic phenotypes occur during acquisition of resistance to P-AscH. Cells resistant to P-AscH demonstrated increased invasive potential, more aggressive tumor colonization, and higher abundance of circulating tumor cells in vivo. Our data support that resistance to oxidative stress enhances metastatic disease and indicates a potential route for PDAC to tolerate high levels of P-AscH and may explain why some patients do not respond to this treatment regimen.