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P78. Casein kinase II inhibition with proteosome inhibition demonstrates therapeutic potential in gastroenteropancreatic neuroendocrine tumor liver metastases via abrogation of NFκB signaling

Thursday, March 5, 2026
4:37 PM - 4:44 PM MST
Location: 105A-C
Introduction

NFκB signaling has been implicated in metastasis and everolimus resistance in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). However, therapeutic exploitation has remained elusive. Casein kinase II (CK2) emerged as a novel target from our prior phosphoproteomic analysis of GEP-NET liver metastases and has a defined role in NFκB signaling through p65. Moreover, our lab has investigated hepatic regional delivery methods for proteasome inhibitors, which have shown efficacy in NFκB inhibition via 26S proteasome inhibition. We therefore sought to determine if combining CK2 inhibition with proteasome inhibition may effectively target NFκB signaling in GEP-NETs.

Methods

Patient-derived organoids (PDOs) were created, with drug response measured by CellTiter-Glo and fluorescent imaging 96 hours post-treatment. Matched ex vivo patient tumor-slice culture models were generated for signal transduction studies. Immunoblotting of patient tumor-slices was completed 6 hours post-treatment with CK2 inhibition (silmitasertib, Sil), proteasome inhibition (carfilzomib, CFZ), or combination (Sil:CFZ; 2000:1).

Results

To evaluate the combination of Sil:CFZ, we assessed cytotoxic response in 9 small bowel NET (SBNET) and 10 pancreatic NET (PNET) liver metastasis PDOs (Figure 1A-B). Sil:CFZ was more effective than Sil alone [SBNET: mean 2.7 µM vs. 6.5 µM (p=0.02); PNET: mean 2.0 µM vs. 5.3 µM (p=0.02)] or CFZ alone [SBNET: mean 1.4 nM vs. 9.3 nM (p=0.02); PNET: mean 1.0 nM vs. 12.2 nM (p=0.03)]. Ex vivo validation of combination CK2 and CFZ inhibition was undertaken utilizing a tumor-slice perfusion model to study NFκB signal transduction. Sil demonstrated efficacy in reducing expression of phospho-NFκB S529 and S536 in GEP-NET liver metastases. Furthermore, combined Sil:CFZ treatment resulted in lower expression of phospho-NFκB (S529 and S536) compared to Sil or CFZ alone (Figure 1C).

Conclusions

Combination Sil:CFZ therapy demonstrates potential improved therapeutic efficacy and increased down-modulation of NFκB signaling compared to CK2 or proteasome inhibition alone. These findings suggest translational utility of leveraging patient-derived ex vivo models for drug discovery.

Learning Objectives:

  • To assess the role of casein kinase 2 in GEP-NETs
  • To determine the enhanced cytotoxicity of combination therapy targeting casein kinase 2 and proteasome activity
  • To learn the applications of ex-vivo models in novel therapy and signaling transduction