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

TL;DR

This study explores carfilzomib as a potential treatment for gastric cancer by targeting the PSMB8 protein, which is elevated in cancer cells and linked to poor survival.

Contribution

The study identifies PSMB8 as a novel therapeutic target and repurposes carfilzomib as a drug with anti-tumor activity in gastric cancer.

Findings

Carfilzomib inhibited tumor growth in a mouse model of gastric cancer.

The drug induced apoptosis and reduced cell proliferation in cancer cells.

PSMB8 is elevated in gastric cancer patient samples and is associated with poor survival.

Abstract

Gastric cancer (GC) is often detected at advanced stages, leading to a need for effective targeted therapies. In this study, we identified Psmb8 as a putative therapeutic target based on gene expression profiling from our accelerated Helicobacter-induced gastric cancer mouse model. We observed elevated levels of PSMB8 in both a human GC epithelial cell line and patient samples. Thereafter, we identified carfilzomib as a drug that selectively targets PSMB8 and tested its efficacy on a human-cell-line-derived xenograft model. Carfilzomib inhibited tumor growth by inducing tumor cell loss via apoptosis and impeding cell proliferation. This suggests that it has robust anti-tumor activity and has potential to be used as a treatment for cancers where high levels of PSMB8 are associated with poor overall survival.

Background/Objectives: Identifying novel targets to treat gastric cancer (GC) has become a focus of research in recent years. Our accelerated Helicobacter-induced gastric cancer mouse model allowed us to identify several differentially expressed genes (DEGs), including Psmb8 (proteasome subunit beta type 8, also called Lmp7), which was also found to be elevated in GC patient samples. PSMB8 encodes one of the immune subunits of the immunoproteasome, which has been associated with disease severity in multiple cancers. Methods: We identified carfilzomib from a public database as a potential drug targeting PSMB8; 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. Results: We observed that carfilzomib retarded tumor growth, inhibited cell proliferation, and induced apoptosis. Conclusions: These results strongly suggest that PSMB8 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 PSMB8 are associated with poor overall survival.

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