EXPRESSION PROFILING OF NOVEL THERAPEUTIC TARGETS IN GASTRIC CANCER

EXPRESSION PROFILING OF NOVEL THERAPEUTIC TARGETS IN GASTRIC CANCER

• Author
• Polyana Silva de Araújo
• Co-authors
• Taíssa Maíra Thomaz Araújo , Fabiano Cordeiro Moreira , Samir Mansour Moraes Casseb , Lívia Érika Carlos Marques , Louise Sousa de Souza , Rommel Rodríguez Burbano , Paulo Pimentel de Assumpção
• Abstract

• Introduction: Gastric cancer (GC), a significant global health burden, records approximately 1 million annual incident cases. Early detection through comprehensive diagnostic modalities is critical for optimizing therapeutic outcomes. Standard management of locally advanced GC involves surgical resection, combined with systemic therapies. Minimally invasive surgical approaches are increasingly adopted for resectable disease, while advanced stages benefit from immune checkpoint inhibitors and molecularly targeted therapies. Emerging therapeutic strategies, including novel targeted agents and next-generation immunotherapies, demonstrate potential for enhancing survival and quality of life. Objective: This study evaluates the expression of therapeutic targets for advanced GC - HER2, TROP2, VEGF, CLDN18.2, FGFR2, PD-1, PD-L1, VEGFR2, CTLA-4 and TIGIT - in gastric tissue samples with and without cancer. These targets are currently under investigation for novel pharmacological agents in ongoing clinical trials. Methods: A total of 124 GC and 62 adjacent to tumor (ADJ) samples from patients who underwent surgical resection, and 20 metaplasia (MP) samples obtained via endoscopic biopsy were analyzed. RNA-seq was conducted in a paired-end manner on the NextSeq® platform (Illumina®). The NextSeq® 500 MID Output V2 kit – 150 cycles (Illumina®) was used according to the manufacturer’s instructions. Human transcript reads were characterized through alignment and quantification using Salmon v1.5.2, with the coding transcripts from hg v38 (www.ensembl.org) as the reference index and GENCODE v.42 (www.gencodegenes.org) as annotation. The reads were imported from Salmon into RStudio using the Tximport v3.14.0 package. Results: HER2, FGFR2, VEGFR2, CLDN18.2 (p<0.0001), TROP2 and VEGF (p<0.001, Kruskal-Wallis test, adjusted by Benjamini-Hochberg) expression is significantly elevated in GC and ADJ compared to MP. Notably, patients with high FGFR2 expression showed greater survival (p<0.05, Kaplan-Meier). PD-L1 expression, by the way, was significantly higher in MP, compared to GC and ADJ. There was no statistical difference in the expression of CTLA-4, TIGIT, and PD-1 genes between samples. Conclusion: Elevated HER2, FGFR2, VEGFR2, CLDN18.2, TROP2, and VEGF levels in GC and ADJ reflect their well-documented roles in tumor proliferation, angiogenesis, and metastasis, which are currently being explored as therapeutic vulnerabilities. The significant association between high FGFR2 expression and improved survival contrasts with the majority of published studies that link FGFR2 overexpression to poor prognosis. However, some evidence demonstrates that FGFR2 activation can upregulate immune-modulating molecules like PD-L1 through the MAPK, PI3K and JAK/STAT3 pathways, potentially enhancing anti-tumor immunity by increasing immune cell infiltration. This immune-modulating effect may provide a plausible explanation for our observation and highlights the complex, multifaceted role of FGFR2 in cancer biology. Interestingly, the higher PD-L1 expression in MP compared to GC and ADJ may indicate an early immune evasion mechanism or a distinct local immune microenvironment, warranting further investigation. The lack of differential expression for CTLA-4, TIGIT, and PD-1 suggests that these immune checkpoints might play prominent roles in the early phases of gastric tumorigenesis, potentially explaining the mixed clinical responses to checkpoint blockade therapies in this setting. Collectively, these findings underscore the importance of molecular stratification in guiding personalized therapeutic strategies for GC, with ongoing trials likely to refine these approaches further.

• Keywords
• Gastric cancer, Carcinogenesis, Novel targets, Therapy
• Modality
• Pôster
• Subject Area
• Molecular Studies

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