Establishment of panapoptotic gene signatures of platinum-chemotherapy to predict the response of chemotherapeutic drug resistance in gastric cancer

Purpose Gastric cancer (GC) remains a daunting problem because of its inherent resistance to chemotherapy, particularly platinum-based medicines. This work was undertaken to discover the molecular foundations of the involvement of PANoptosis-related genes (PANRGs) in platinum-chemotherapy for GC. Methods A comprehensive bioinformatics analysis of platinum-chemotherapy resistance of GC was conducted in the dataset GSE66229 from the Tumor Cancer Genome Atlas (TCGA). The RNA sequencing data were normalized, and differential expression analysis was performed to identify PANRGs that distinguish platinum-sensitive from-resistant GC. Subsequent GO functional and KEGG pathway analyses were conducted to elucidate the biological relevance of these genes. Furthermore, a prognostic model was constructed to predict survival outcomes in GC patients utilizing the identified PANRGs. Chemotherapeutic drug sensitivity analysis was performed using the Cancer Drug Sensitivity Genomics (GDSC) database. Results The analysis yielded 18 PANRGs that were significantly differentially expressed in platinum-resistant GC comparing to platinum-sensitive GC, which includes upregulated genes, CASP9, CHMP6, BAG3, EYA2, HSPB1, SHH, SLC9A3R1, SMAD3, and FTH1, and downregulated genes, TP53, ADORA1, CAAP1, CHEK2, DAP3, INHBA, URI1, YWHAH, and XIAP. These genes were significantly enriched in biological processes and pathways associated with cell cycle, apoptosis, and platinum drug resistance. Based on the expressions of DAP3 and XIAP from single factor analysis, the prognostic model accurately stratified patients into high- and low-risk groups, with distinct survival differences identified. The model was verified on an independent GEO dataset, demonstrating its resilience and generalizability. AZD6738, Dihydrorotenone, Paclitaxel, MK-1775, Osimertinib, Ulixertinib, AZD2014, Cytarabine, PD0325901, and Wee1 inhibitors were the top ten chemotherapeutic medicines (comparison of IC50 between sensitivity and resistance groups, P < 0.05). Conclusion This finding underscores the pivotal role of PANoptosis in modulating platinum-chemotherapy resistance in GC. DAP3 and XIAP were evaluated as prognostic models.