E201: TAK-981 Synergizes with Cytotoxic and Targeted Therapy in Patient Derived Organoid Models of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) has minimal response to single agent chemotherapy and responses to multiagent therapies are generally short-lived and associated with profound toxicity. Therefore, identification of synergistic multi-agent chemotherapy regimens that minimize toxicities is an unmet need. Sumoylation is a post translational modification, which has been implicated in cell cycle regulation and innate immune response. TAK-981, a small molecule targeting SUMO activating enzymes 1 and 2, has been shown to the impair DNA damage repair, upregulate IFN regulated genes and augment innate immune response. Current clinical trials of TAK-981 focus on combination with immunotherapy for hematologic malignancies or use as a single agent for solid tumors. However, drug synergy between TAK-981 and standard of care chemotherapies for PDAC has not been investigated.

Methods: Two PDAC patient derived organoids (PDOs), hf44 and hm1e, were exposed to media containing combinations of TAK with gemcitabine (G), irinotecan (I), cisplatin (C), and the Kras G12D inhibitor MRTX1133, for 24 hours. Media was then exchanged and PDOs were incubated for an additional 2 days or 4 days in drug-free media. Cell viability was assessed at these timepoints using CellTiter Glo. Synergy plots and dose response curves were generated using Combenefit, a drug synergy mapping software package.

Results: Synergy was observed in all TAK combinations. Under all conditions, the drug response in both PDOs was similar. Of the four drug combinations with TAK, MRTX1133 and irinotecan demonstrated the greatest degree of synergy at both the 2-day and 4-day timepoints. 24 hrs of drug exposure was sufficient to induce sustained cell death, as cultures were unable to recover, even 4-days after drug exposure had ceased. Synergy plot comparison at 2-days and 4-days demonstrated that regions of synergy identifiable at 2-days were augmented at 4-days. TAK+MRTX1133 showed synergy at higher MRTX1133 dose ( >0.05µM), across all doses of TAK. TAK+I showed the greatest synergy for mid-range doses for both TAK (0.01µM-0.1µM) and I (0.001µM-0.1µM). TAK+C demonstrated synergy at high C doses ( >1µM) and low TAK doses (min. 0.001µM). TAK+G showed synergy at low concentrations of G (min. 0.0043 µM) and across all doses of TAK.

Conclusions: Treatment of PDAC PDOs with low dose TAK combination therapy leads to sustained drug synergy even at 4-days after initial drug exposure. Treatment of PDAC with TAK and chemotherapy/targeted therapy combinations is a promising therapeutic strategy that warrants further investigation.