Repurposing proteasome inhibitors in the treatment of esophageal squamous cell cancer

Background. Esophageal squamous cell cancer (ESCC) is characterized by poor prognosis and limited options due to the lack of general effective chemotherapy method. Immune and targeted therapy have made progress in recent years, but only a few patients can benefit from them. Methods. In this study, a high-throughput in vitro drug sensitivity screening was conducted on four esophageal squamous cell carcinoma (ESCC) cell lines using a library of 1,600 FDA-approved compounds to identify potential proteasome inhibitors (PIs) for ESCC therapy. Subsequently, the responsiveness of ESCC cell lines to PIs was characterized, enabling the identification of effective two-drug combinations. Six ESCC cell lines and two control cell lines were treated with 15 drugs as monotherapies, and promising two-drug combinations were predicted using the IDACombo algorithm. The synergistic effects of these combinations were then assessed with SynergyFinder in three ESCC cell lines and one control line. Finally, the anticancer efficacy of the selected drug candidates was validated in patient-derived organoid (PDO) models of ESCC. Results. Monotherapy identified nine more effective drugs (carfilzomib, bortezomib, MG-132, Ixazomib citrate, MLN-2238, oprozomib, oxaliplatin, anlotinib and delanzomib) across all ESCC cell lines, of which carfilzomib, bortezomib, MG-132, Ixazomib citrate, MLN-2238 and oprozomib were highly potent drugs in ESCC cells. In addition, we found that the synergistic effect of carfilzomib and anlotinib was better than other drug combinations in the combination therapy. Conclusions. Taken together, we show that PIs are promising compounds in the treatment of ESCC. Moreover, anlotinib used in combination with carfilzomib exhibits increased efficiency.