Drug repurposing identifies proteasome inhibitors as antiproliferative agents counteracting inflammation-driven chemoresistance in triple-negative breast cancer organoids

Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options, high relapse rates, and poor survival outcomes, largely due to chemoresistance. This study aimed to identify potential therapeutic strategies by repurposing FDA-approved anticancer drugs using patient-derived TNBC organoids from drug-resistant residual tumors post-chemotherapy. A high-throughput screen of 133 FDA-approved drugs, integrating image-based analysis and drug-sensitivity assays, identified the proteasome inhibitors bortezomib and carfilzomib as potent cytotoxic agents. Proteomic analysis, coupled with translation and cell cycle assays, showed that these inhibitors suppress TNBC organoid growth by downregulating ribosomal protein expression, leading to impaired translation and disrupted cell cycle progression. Furthermore, drug response dynamics confirmed their efficacy in overcoming clinical drug resistance. Transcriptomic profiling revealed that proteasome inhibitors counteract doxorubicin-induced, inflammation-driven resistance through dual anti-inflammatory and antiproliferative effects. Collectively, these findings support proteasome inhibition as a promising therapeutic strategy to overcome chemoresistance in TNBC.