Abstract 4709: Enhancing chemotherapy efficacy in pancreatic cancer synergistic effects of ONC206 and ONC212 with 5-FU through inhibition of p-ERK

Abstract Background: Pancreatic cancer is a lethal malignancy projected to become the second leading cause of cancer deaths by 2030, with a 5-year survival rate of just 12%. Resistance to chemotherapy, particularly 5-fluorouracil (5-FU), remains a major challenge in treating pancreatic ductal adenocarcinoma (PDAC). ONC206 and ONC212, imipridone-class agents targeting DRD2/ClpP and GPR132/ClpP, show promise in disrupting tumor growth and inducing apoptosis. Phosphorylated ERK (p-ERK), a key driver of PDAC aggressiveness via the MAPK pathway, is a critical therapeutic target. We hypothesize that combining ONC206 or ONC212 with 5-FU could enhance efficacy by synergistically inhibiting p-ERK, supporting their potential in PDAC treatment. Materials & Methods: The synergy of ONC206 or ONC212 with 5-FU was tested in PDAC cell lines (PANC1, CFPAC-1, HPAF-II, CAPAN-2, ASPAC1) using CellTiter-Glo for cell viability at 72 hours. Western blotting assessed p-ERK, ATF4, and other key proteins for pathway inhibition. Results: Synergy between 5-FU and ONC212, or 5-FU and ONC206, was observed across all cell lines, with IC50 values for ONC206 ranging from 300-500 nM and for ONC212 from 70-100 nM. At the 48-hour time point in the HPAF-ll cell line, 100 nM ONC212 significantly inhibited p-ERK levels compared to 300 nM ONC206. Both treatments as monotherapies resulted in reduced p-ERK levels compared to control. When combined with 25 µM 5-FU, ONC212 caused a more pronounced reduction in p-ERK. In the PANC-1 cell line, the strongest reduction in p-ERK was observed with the combination of ONC212 and 5-FU at 48 hours. In the ASPAC1 cell line, p-ERK inhibition occurred only in conditions containing ONC212, with a more significant effect when combined with 5-FU. Conclusions: Our data demonstrate that combining 5-FU with ONC206 or ONC212 results in the inhibition of p-ERK, a critical node in the PDAC growth pathway. This synergy between 5-FU and the imipridone compounds ONC206 and ONC212 is a universal phenomenon in the tested human PDAC cell lines. Notably, ONC212 is more potent than ONC206, allowing for lower dosages, and in cases where ONC206 does not effectively inhibit p-ERK, ONC212 can be a more effective option Further studies are needed to elucidate the exact mechanism of this synergy, but these findings provide a promising foundation for developing novel combination therapies to improve PDAC treatment outcomes. Citation Format: Vida Tajiknia, Claire Lin, Maximilian Pinho-Schwermann, Connor Purcell, Sean Lawler, Wafik El-Deiry. Enhancing chemotherapy efficacy in pancreatic cancer synergistic effects of ONC206 and ONC212 with 5-FU through inhibition of p-ERK [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4709.