Investigating the Roles of MAPKs as Precision Oncology Targets: A Multi‐cancer Expression and Survival Study

Background/Aim: Cancer remains a leading cause of mortality globally, driven by complex molecular mechanisms and characterized by significant biological heterogeneity across cancer types. We aimed to discover mitogen-activated protein kinases (MAPKs) family members as both biomarkers and therapeutic targets in different cancer types. MAPKs are key signaling molecules regulating cell proliferation, differentiation, stress response, and apoptosis. Dysregulation of MAPK pathways has been implicated in the onset and progression of multiple cancers, contributing to tumor growth, metastasis, and therapeutic resistance. Given their diverse roles across cancer types, systematic analysis of MAPK gene expression, mutations, and interactions with tumor microenvironment is essential. Materials and Methods: The present study undertakes a comprehensive transcriptomic analysis of MAPKs in nine major cancer types using RNA-Seq datasets from The Cancer Genome Atlas (TCGA). RNA-Seq data were analyzed to identify differentially expressed MAPKs across nine cancer types using DESeq2, NOIseq, and limma. Significant genes (adjusted p<0.05) were subjected to GO and KEGG enrichment (EnrichR), mutational profiling (cBioPortal), and Kaplan-Meier survival analysis. Tumor immune infiltration was further assessed using TIMER2.0 to explore immune– gene interactions. Results: Through rigorous differential expression analysis, we identified key MAPKs that are significantly altered in liver hepatocellular carcinoma (LIHC) and lung adenocarcinoma (LUAD). Specifically, six MAPKs (MAPK3, MAPK7, MAPK9, MAPK10, MAPK12, and MAPK13) were found to be differentially expressed in LIHC, while MAPK6 emerged as the sole significant candidate in LUAD. Functional enrichment and pathway analysis revealed that these MAPKs are involved in critical oncogenic pathways, including MAPK-mediated transcriptional regulation and stress-activated signaling cascades. Mutational profiling and survival analysis further validated the prognostic significance of these genes, with several MAPKs showing strong associations with reduced patient survival. Tumor immune infiltration analysis indicated potential roles of these MAPKs in modulating immune responses within the tumor microenvironment. Also, MAPKs identified in this study are structurally related, suggesting that targeting them collectively may enhance therapeutic efficacy and overcome resistance mechanisms. Conclusion: Our integrated approach underscores the value of MAPK family members as both biomarkers and therapeutic targets in LIHC and LUAD. This study contributes important insights into MAPK-related oncogenic processes and supports the development of targeted therapies under the framework of precision oncology.