What question did this study set out to answer?

To investigate the effect of combining SUMO inhibition with irinotecan on pancreatic cancer cytotoxicity.

April 5, 2026Cancer Research0 citations

Abstract 5767: Combining SUMO inhibition and irinotecan increases pancreatic cancer cytotoxicity

ACAsimina Courelli LRLi RenBengbu Medical College HTHerve Tiriac

Key Points

To investigate the effect of combining SUMO inhibition with irinotecan on pancreatic cancer cytotoxicity.
Used human single-cell RNA sequencing to identify SUMO2/3 expressing cancer cells.
In vitro experiments with murine PDAC cells treated with SST and/or IRI to assess cell viability and apoptosis.
Conducted western blotting to analyze proteins related to apoptosis and Top-1 efficacy.
Performed in vivo survival experiments with NSG mice to evaluate tumor growth and survival with SST and IRI treatment.
Analyzed human PDAC cultures to assess the effects of SST and IRI on cancer cell markers.
SUMO2/3 is highly expressed in PDAC cells compared to normal tissue, persisting after treatment.
Combined SST and IRI treatment showed significant in vitro synergy, reducing cell viability as low as 50nM.
In vivo, SST+IRI treatment improved survival (24 days) compared to IRI alone (16 days) and reduced tumor volume significantly.
Human PDAC slices treated with SST+IRI showed the greatest reduction in PANCK+ and EPCAM+ cancer cells, at 9.5%.

Abstract

Abstract Introduction: Pancreatic cancer (PDAC) has a transient response to chemotherapy, motivating the need for improved treatment options. Irinotecan (IRI) is a standard of care agent for both 1st and 2nd line PDAC therapy. SUMOylation is a post translational modification on topoisomerase 1 (Top-1) that modulates its DNA binding. We hypothesized that combining IRI with Subasumstat (SST—a SUMOi agent) would synergize in reducing Top-1 efficacy, leading to augmented apoptosis. Methods: Human single cell RNA sequencing (scRNASeq): using the Human Pancreatic Cancer Single-Cell Atlas to identify SUMO2/3 expressing cancer cells after FOLFIRNINOX. In Vitro Synergy: KPC46, FC1245, FC1245-Gem Resistant murine PDAC cells treated with IRI and/or SST (1nM-500nM, 24hrs); viability assessed with cell titer glo; synergy plots generated using Combenefit. Western Blots (WB): KPC46 and FC1245 cells treated with SST and/or IRI (100nM) for 24 hours; probed for Top-1 (chromatin protein fraction), γ-H2AX, and cleaved caspase-3 to validate apoptosis. Survival Experiments: NSG mice underwent orthotopic KPC46 cell injections—IP injections with SST (15mg/kg q48h) and/or IRI (12.5mg/kg qwkly); tumor volume (TV) assessed with ultrasound. Human PDAC Cultures: patient tumor slices incubated in 200nM SST and/or IRI for 5 days; flow Cytometry (FC) conducted for EPCAM and PanCK PDAC cell markers. Results: 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 treatment. Significant in vitro synergy between SST+IRI occurred as low as 50nM. WB showed the greatest increase in chromatin bound Top-1, total cell ϒ- H2AX, and cleaved caspase 3 (Band Intensity: IRI: 0.1, SST:0.15, SST+IRI: 0.52; p=0.009) occurred for SST+IRI. Synergistic cytotoxicity of SST+IRI treatment in vivo resulted in significantly improved survival (IRI:16, SST:17, SST+IRI=24 days; p=0.008) and reduced TV (after 2 wk-treatment; AvgTV: IRI=358mm3, SST all mice dead, SST+IRI=132mm3; p=0.001). In human PDAC slices, SST+IRI treatment yielded the greatest decrease in PANCK+ and EPCAM+ cells (IRI:24.4%, SST:15.5%, SST+IRI:9.5%). Conclusion: SST+IRI constitutes a promising combination treatment for PDAC with synergistic PDAC cytotoxicity observed in both murine and human models. Clinically, SST could serve as an adjunct to FOLFIRINOX or SST+IRI could be an alternative 2nd line treatment with potential to include a RAS inhibitor. Citation Format: Asimina Courelli, Leonie Ren, Herve Tiriac, Yuan Chen, Andrew Lowy. Combining SUMO inhibition and irinotecan increases pancreatic cancer cytotoxicity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5767.

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