Repurposing Carfilzomib as a Promising Drug for Targeted Therapy in Gastric Cancer

<b>Background/Objectives</b>: Identifying novel targets to treat gastric cancer (GC) has become a focus of research in recent years. Our accelerated <i>Helicobacter</i>-induced gastric cancer mouse model allowed us to identify several differentially expressed genes (DEGs), including <i>Psmb8</i> (proteasome subunit beta type 8, also called Lmp7), which was also found to be elevated in GC patient samples. <i>PSMB8</i> encodes one of the immune subunits of the immunoproteasome, which has been associated with disease severity in multiple cancers. <b>Methods:</b> We identified carfilzomib from a public database as a potential drug targeting <i>PSMB8</i>; it effectively halts immunoproteasome activity, leading to apoptosis. We tested carfilzomib's efficacy against gastric cancer by subcutaneously implanting nude mice with human gastric epithelial-derived tumors and treating them with carfilzomib, either alone or in combination with 5-fluorouracil (5-FU), a standard-of-care drug. The effectiveness of drug treatment was measured by tumor growth, cell proliferation, and apoptosis. <b>Results:</b> We observed that carfilzomib retarded tumor growth, inhibited cell proliferation, and induced apoptosis. <b>Conclusions:</b> These results strongly suggest that <i>PSMB8</i> is a suitable candidate for targeted therapy. Moreover, with carfilzomib having robust anti-tumor activity, it has potential as a treatment option for cancers where high levels of <i>PSMB8</i> are associated with poor overall survival.