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 promising therapeutic target. Accordingly, our laboratory has developed NUPR1 inhibitors such as ZZW-115. In this study, we developed a ZZW-115 resistance model in MiaPaCa-2 cells by applying repeated cycles of drug exposure and recovery, yielding a subpopulation (Resistant(+) MiaPaCa-2 cells) that overexpresses the target gene NUPR1. These cells exhibit multiple 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, certain cellular and molecular changes persisted, highlighting tumor plasticity and the complexity of adaptive mechanisms as observed in (Resistant(+) compared to Resistant(-) MiaPaCa-2 cells). Transcriptomic analysis revealed activation of survival and repair pathways (p53, UPR) alongside suppression of rapid-proliferation and conventional lipid metabolism pathways, resulting in a “reinforced survival” phenotype in Resistant(+) MiaPaCa-2 cells. Remarkably, NUPR1 overexpression played a pivotal role in acquiring resistance by strengthening cellular defenses against ZZW-115’s cytotoxic effects. Collectively, these adaptations converge to form a “reinforced survival” phenotype, underscoring the complex and multifaceted nature of therapeutic resistance in pancreatic cancer cells. Targeting NUPR1 signaling and metabolic reprogramming may therefore represent a critical strategy for overcoming drug resistance and improving treatment outcomes. The resistance model established here provides a valuable tool for investigating combination approaches to overcome drug resistance in PDAC.