Abstract 955: Double-targeting of pancreatic ductal adenocarcinoma (PDAC): Unveiling the potent combination of NMS-873 and BAY-876

Abstract Pancreatic ductal adenocarcinoma (PDAC) stands out as one of the most aggressive and challenging-to-treat cancers known. Consequently, the development of effective therapeutic strategies holds significant importance in enhancing patient outcomes. In contrast to single-drug treatments, combination therapies offer the potential for improved results by addressing multiple pathways. This approach not only reduces the likelihood of drug resistance but also encourages synergistic effects, all while permitting the use of lower individual drug doses, thus minimizing potential side effects. In this study, we subjected a panel of PDAC cell lines with varying degrees of sensitivity to a high-throughput combinatorial drug screen. Mitochondrial complex 1/p97 inhibitor NMS-873 was tested in combination with 95 other compounds, revealing remarkable synergy when paired with Glut1 inhibitor BAY-876. In order to affirm the validity of these findings, we conducted further experiments involving multi-dose drug combinations within long-term clonogenic assays. These supplementary investigations also demonstrated significant synergistic effects between BAY-876 and NMS-873, as quantified through the calculation of Bliss and Zip scores. Notably, this combination exhibited superior efficacy when confronting PDAC cell lines that are more resistant to NMS-873, highlighting the potential of this combination to overcome therapy resistance. To gain insights into the underlying mechanisms behind these outcomes, we performed a gene enrichment analysis which revealed that the more sensitive cell lines exhibited elevated rates of cell division, while the more resistant ones demonstrated heightened cRNA processing and increased metabolic activity, particularly in protein, phospholipid, and lipid synthesis. The combination of BAY-876 and NMS-873 presents a promising avenue for the targeted treatment of PDAC. This study underscores the remarkable synergy observed in mouse PDAC cell lines with a particular emphasis on the heightened efficacy against cell populations that are more resistant to NMS-873. These results warrant further investigation to elucidate the underlying molecular mechanisms and validate these findings in clinical settings. Citation Format: Emily Rita Eppinger, Christian Schneeweis, Dieter Saur. Double-targeting of pancreatic ductal adenocarcinoma (PDAC): Unveiling the potent combination of NMS-873 and BAY-876 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 955.