Key Protein MEST Identified in Gastric Cancer Growth, Inhibited by AIDS Drug Cobicistat
Background
Gastric cancer (GC) is a highly lethal intractable disease with a high mortality rate worldwide. Conventional treatment methods have shown limited and inconsistent response rates due to genetic diversity among patients, and overcoming drug resistance remains a clear limitation. The lack of directly applicable target molecules for clinical use continues to be a major obstacle in overcoming GC. Recently, academic research has focused on the tumor microenvironment, which regulates cancer progression and metastasis. Among these, the Mesoderm-Specific Transcript (MEST) has been identified as a key factor deeply involved in tumor-activating signaling pathways. However, the precise molecular mechanisms of MEST in the process of GC development and its therapeutic applications have not yet been fully elucidated. Research to clarify these mechanisms and to explore effective inhibitory compounds is urgently needed.
Key Findings
The research team conducted a detailed analysis of the correlation between MEST expression patterns and patient outcomes using gastric cancer tissue microarray analysis. The results showed that MEST is abnormally overexpressed in GC tissues compared to normal tissues, and higher expression levels were significantly associated with lower survival rates. In GC cell lines where the MEST gene was knocked out using CRISPR/Cas9 technology, cell proliferation and migration were markedly suppressed. In cell-derived xenograft (CDX) mouse model experiments, tumor growth was clearly delayed in the MEST gene-knockout group compared to the control group. The research team further elucidated the specific mechanism by which MEST activates the key pathway for tumor growth, the nuclear factor kappa B (NF-κB) signaling pathway, through transcriptome analysis.
Furthermore, the research team attempted to discover new drug candidates that inhibit MEST by combining structure-based virtual screening techniques with surface plasmon resonance (SPR) binding experiments. After screening various compounds, they discovered that cobicistat, a drug previously approved for the treatment of AIDS, strongly binds to the MEST protein. Cobicistat was found to block MEST activity and inhibit the activation of the NF-κB pathway at its source. The drug's excellent therapeutic effects were observed not only in GC cell lines but also in organoid models that mimic patient tissues and patient-derived xenograft (PDX) animal models. In the xenograft models treated with cobicistat, tumor cell growth was stably suppressed without any toxic reactions.
Significance and Prospects
This study is being evaluated as a new breakthrough in the treatment of gastric cancer, which has a high unmet medical need. By newly discovering the anti-cancer efficacy of cobicistat, a drug previously marketed for other diseases, it has established a model case for drug repurposing, which can significantly shorten the average drug development period from over 10 years to a few years and reduce associated costs. It is also observed that the clinical phase 2 entry barrier is relatively low due to the already verified safety profile from toxicity assessments.
However, since cobicistat may interact with other biological molecules besides MEST, additional verification procedures to precisely analyze target selectivity are required. Because MEST expression varies greatly among patients, companion diagnostic technology development must be pursued in parallel to maximize therapeutic efficacy in actual treatment. The follow-up research team plans to conduct formulation studies to improve the drug's absorption rate and bioavailability, aiming to accelerate its clinical application.
BACKGROUND: Gastric cancer (GC) constitutes a substantial global public health challenge, and the lack of tractable molecular targets limits therapeutic progress. Mesoderm-Specific Transcript (MEST) has been implicated in tumor-related signaling, yet its functional role and druggability in GC remain undefined. METHODS: The analyses of GC tissue microarrays and cohorts were performed to evaluate MEST expression and its clinical significance. CRISPR/Cas9-mediated MEST knockout was used to characterize its oncogenic functions in GC cells and xenograft models. Integrated RNA sequencing and pathway analysis was utilized to elucidate signaling pathways under the regulation of MEST. A structure-guided virtual screen combined with SPR binding and phenotypic assays were employed to discover small molecules targeting MEST. The therapeutic effects and mechanism of the lead compound were evaluated using GC cell lines, patient-derived organoids, cell-derived xenograft (CDX), and patient-derived xenograft (PDX) models. METHODS: MEST expression in GC tissues was elevated and linked to poor prognosis. Functionally, genetic ablation of MEST impaired GC cell proliferation, invasion, migration, and suppressed tumor growth in CDX models. Screening of approved-compound libraries identified cobicistat as a previously unrecognized high-affinity candidate MEST-inhibitory compound. Cobicistat suppressed tumor growth across a panel of preclinical GC models, including cell lines, organoids, CDX and PDX. Mechanistically, MEST may drive GC progression by activating the NF-κB pathway, whereas cobicistat may antagonize MEST binding and blocked NF-κB pathway. CONCLUSION: MEST functions as a key oncoprotein driving GC progression via NF-κB activation. Cobicistat, a candidate MEST-inhibitory compound, exhibits favorable preclinical efficacy and safety, providing a promising candidate for targeted GC therapy.
The results of this study provide a concrete clinical treatment scenario for improving the survival rate of gastric cancer patients. It is now possible to precisely select patient groups with overexpression of the MEST protein among existing GC patients and immediately apply a personalized targeted drug therapy based on cobicistat. Since cobicistat is already an FDA-approved drug available on the market, it is relatively easier to enter clinical trials compared to new target drugs. This is the reason why clinical trials aimed at expanding the drug's indication for GC treatment can be rapidly initiated. This drug is particularly evaluated as an alternative for improving treatment outcomes in patients with recurrent GC who do not respond to standard chemotherapy, as it demonstrates synergistic anti-cancer effects when administered in combination with standard chemotherapeutic agents. By blocking the activation of the NF-κB pathway, it suppresses the acquisition of drug resistance pathways in tumors.