Abstract A139: SUMOylation Inhibition Synergizes with Irinotecan and Daraxonrasib to Treat Pancreatic Cancer

Abstract

Introduction: Pancreatic cancer (PDAC) has a poor response to standard cytotoxic chemotherapy, necessitating improved treatment options. SUMOylation is a post-translational modification (PTM) that modulates cell cycle replication, cell proliferation, and DNA damage repair pathways. We hypothesized that SUMOylation inhibition agent (SUMOi; SB-4826) would synergize with cytotoxic chemotherapies and daraxonrasib (DARA) to increase cancer cell death. Methods: In Vitro Synergy: Human PDAC organoid lines(hf44, hf23, hT1- primary tumor; hm1a, hm1e, hm1f- lung metastases; hm19b- liver metastases) screened with 5-Fluorouracil, Irinotecan (IRI), Oxaliplatin, Gemcitabine, Paclitaxel in combination with SUMOi (100nM max concentration for all drugs). KPC46, FC1245, FC1245-Gem Resistant murine PDAC cells treated with IRI and/or SUMOi (500nM max concentration for all drugs; viability measured using cell titer glo; synergy plots generated using Combenefit. Western Blots (WB): KPC46 and hf44 treated with SUMOi and/or IRI; staining for γ-H2AX and cleaved caspase-3 (CC3). Animal Experiments: NSG and B6 mice underwent orthotopic KPC46, FC1245, and FC1245-GemR cell injections—IP injections with SUMOi, and/or IRI; tumor volume (TV) assessed with ultrasound. Human PDAC Cultures: patient tumor slices incubated in SUMOi 100 mg/kg biweekly, DARA 20 mg/kg daily, and/or IRI 12.5 mg/kg qweek. Enrollment upon tumors reaching 3-5 mm diameter (measured by ultrasound); IF was conducted for EdU and γH2AX. Human single cell RNA sequencing (scRNASeq): using the Human Pancreatic Cancer Single-Cell Atlas to identify SUMO2/3 expressing cells. Results: In vitro synergy between SUMOi+IRI was consistently observed at concenctrations ≤ 50nM for both organoid and murine cell lines. Synergistic cytotoxicity of SUMOi+IRI treatment in vivo resulted in significantly decreased tumor growth in KPC46, FC1245, and FC1245-GemR lines compared to monotherapy and untreated groups in NSG mice. WB using KPC 46 and hf44 (organoid) showed the greatest increase in ϒ- H2AX and CC3 occurred for SUMOi+IRI compared to SUMOi and IRI alone. In tumor slices, SUMOi+IRI treatment yielded the greatest decrease in EdU and increase in γH2AX staining . Human tumor scRNASeq showed SUMO2/3 is highly expressed PDAC primary tumor cells as compared to adjacent normal tissue and that SUMO2/3 expressing cancer cells persist after FOLFIRINOX and Gemcitabine/Paclitaxel treatment. B6 mice with orthotopic FC1245 and FC1245-GemR tumors showed the longest survival and smallest tumors with DARA+IRI+SUMOi treatment compared to DARA alone and IRI+SUMOi. Conclusion: SUMOi+IRI shows synergistic cytotoxicity observed in both murine and human PDAC models. SUMO proteins and PTMs are highly expressed in human PDAC tumors compared to normal tissue. Addition of SUMOi+IRI to DARA leads to improved tumor growth control and survival compared to DARA alone in aggressive murine models. Clinically, SUMOi+IRI could be combined with DARA as a second line therapy for treating PDAC. Citation Format: Asimina Courelli, Mia MacDonald, Ponmathi Panneerpandian, Leonie Ren, Jonathan Weitz, Herve Tiriac, Yuan Chen, Andrew M. Lowy. SUMOylation Inhibition Synergizes with Irinotecan and Daraxonrasib to Treat Pancreatic Cancer [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2): nr A139.