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P100. Continuous exposure to proteasome inhibition leads to increased cytotoxicity in colorectal liver metastases

Saturday, March 7, 2026
9:49 AM - 9:56 AM MST
Location: 105A-C
Introduction: Proteasome inhibition demonstrates promising antitumor activity against colorectal cancer in vitro; however, it has been ineffective against solid tumors in vivo, likely due to the intermittent exposure with subsequent proteasome recovery via new proteasome synthesis.  We postulate that continuous infusion, such as through hepatic artery infusion (HAI) therapy, will lead to sustained proteasome inhibition with resultant cytotoxicity.


Methods: Two lines of patient-derived colorectal liver metastasis (CRLM) organoids were exposed to either intermittent (1 hour) or continuous (48 hour) treatment with carfilzomib (CFZ), a potent irreversible proteasome inhibitor. Organoids were then sequentially processed for measurement of proteasome activity and cell viability (up to 48 hours).  To confirm the feasibility of administering a proteasome inhibitor via HAI, an ex-vivo liver perfusion model was used to treat segments of human liver containing CRLM with arterial administration of CFZ. Ki67 and cleaved caspase-3 (CC3) expression were measured via IHC. 


Results: In CRLM organoids, intermittent exposure (1 hour treatment, 30nM) to CFZ led to immediate suppression of proteasome activity, to less than 50% of control. However, proteasome activity began to recover significantly at later timepoints (12-48 hours).  No changes in cytotoxicity were seen, with organoids demonstrating 100% viability at all timepoints. Following the continuous exposure (48 hour treatment, 30nM), sustained inhibition of proteasome activity was observed at all timepoints, including up to 48 hours after initiation of treatment. After the proteasome had been inhibited for at least 24 hours, significant decreases in cell viability were seen. Using an ex-vivo perfusion model, continuous arterial administration of CFZ was achieved for 48 hours. Human CRLM demonstrated decreased proliferation (Ki67 expression) and increased apoptosis (CC3 expression), while the adjacent normal hepatic parenchyma remained unaffected.  


Conclusions: Continuous exposure to CFZ is necessary for sustained proteasome inhibition, which leads tumor cell apoptosis in CRLMs. Here, we present proteasome inhibitor administration via HAI as a novel mechanism for treating colorectal liver metastases. A phase I clinical trial is forthcoming.

Learning Objectives:

  • Identify the role of the proteasome in maintaining homeostasis and how normal cellular function can be affected by perturbations in proteostasis.
  • Discuss how neoplastic cells have an increased susceptibility to proteasome inhibition compared to normal cells.
  • Identify properties that new pharmacological agents must contain in order to be compatible with hepatic artery infusion therapy.