Mechanisms of induced resistance to the antitumoral agent ZZW-115 in pancreas ductal adenocarcinoma

Drug resistance remains a major obstacle in treating pancreatic ductal adenocarcinoma (PDAC). Nuclear protein 1 (NUPR1), a stress-responsive protein implicated in cancer progression and treatment resistance, represents a potential therapeutic target. Our laboratory has developed NUPR1 inhibitors such as ZZW-115. In this study, we established a ZZW-115 resistance model in MiaPaCa-2 cells by applying repeated cycles of drug exposure and recovery, leading to a subpopulation (Resistant(+) MiaPaCa-2 cells) with increased expression of NUPR1. These cells exhibit various adaptations, including increased mitochondrial activity, maintenance of redox homeostasis, and enhanced tolerance to genotoxic damage. Although partial reversion of resistance was observed upon drug withdrawal, several molecular changes persisted. Transcriptomic analysis revealed upregulation of stress response and survival pathways (p53, UPR) and downregulation of proliferative and metabolic programs, suggesting a "reinforced survival" phenotype. NUPR1 overexpression appears to contribute to the resistance process by enhancing cellular defenses against ZZW-115. These findings suggest that targeting NUPR1 signaling and associated metabolic rewiring could help overcome drug resistance. The resistance model presented may serve as a useful tool to explore combination strategies for improving therapeutic outcomes in PDAC.