Abstract A026: Studying the synergistic potential of a p53 reactivator with ROS-mediated therapies for the treatment of pancreatic cancer

Abstract Introduction: Pancreatic cancer, with a dismal five-year survival rate of just 12%, demands innovative approaches due to its resistance to current therapies. TP53 mutations, present in 75% of patients, make mutant p53 an appealing target. Thus, p53 reactivation, restoring its tumour suppressor functions, represents a promising strategy to address this challenge. While the proposed reactivator has shown efficacy in other malignancies, its potential in pancreatic cancer therapy requires further exploration. Methods: In this project, we have assessed the potential of repurposing a reactivator of mutant p53 protein, to inactivate pancreatic cancer cells. We have performed RNA-sequencing analysis in patient-derived models available in the lab, to study the signalling pathways regulated by the p53 reactivator anticancer activity. We have also studied the possibility to synergistically combine this repurposing strategy with reactive oxygen species (ROS)-mediated therapeutic approaches, as we previously observed p53 reactivation inhibits the glutathione antioxidant pathway. Results: The combination treatment induced synergistic cell death (3-fold increase) compared to monotherapy as evaluated by different molecular assays (e.g. MTT and Live/Death Assay). It also increased ROS levels (Flow cytometry) and induced paraptosis and apoptosis (Western Blot, Tomography Electron Microscopy). The RNA-seq data revealed differential expression of more than 200 genes, confirming the activation of oxidative stress and a cellular response to unfolded proteins. Moreover, Sanger sequencing results demonstrated that the sensibility of each pancreatic model to treatment was dependent on the mutational status of TP53. Conclusion/discussion: The combination therapy of a TP53 reactivator and a ROS mediated therapeutic strategy works synergistically in patient derived models, inducing cell death and changes in the expression of certain RNAs directly involved in unfolded protein response. This pilot study shows that this combination is a feasible strategy to treat pancreatic cancer, setting the path for its testing on in vivo models. Citation Format: Daniel Parra Sánchez, Andrés García-Sampedro, Isabela Laughland, Sylvain Peuget, Galina Selivanova, Stephen P Pereira, Pilar Acedo. Studying the synergistic potential of a p53 reactivator with ROS-mediated therapies for the treatment of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A026.