Clinical and Functional Significance of p38δ (MAPK13) in Lung Cancer

BACKGROUND/AIM: MAPK13 (p38δ) is a frequently identified but often ignored MAP kinase in epithelial gene signatures. This study aimed to characterize p38δ expression in normal and cancerous epithelial tissues, investigate its possible role in epithelial identity, epithelial-mesenchymal transition (EMT), cancer progression, drug resistance, and evaluate its prognostic value. MATERIALS AND METHODS: Quantitative analysis assessed p38δ expression across diverse normal human epithelial tissues and correlated it with epithelial markers in cancer cell lines. A p38δ gene signature was analyzed for pathway enrichment in epithelial processes. p38δ expression was compared between epithelial and mesenchymal lung cancer models and in EGFR inhibitor-resistant cells. Prognostic data on cancer patient survival was collected for various cancer types. Functional studies included p38δ knockdown to evaluate EMT markers, E-cadherin/EpCAM, Vimentin and proliferation, and exogenous p38δ expression to assess cell growth/migration. p38δ mRNA and protein levels were measured in Osimertinib-resistant cell lines. RESULTS: p38δ was predominantly expressed across diverse normal epithelial tissues and correlated strongly with epithelial markers in cancer cells. Its gene signature enriched pathways vital for epithelial architecture, adhesion, and differentiation. p38δ was consistently higher in epithelial-enriched lung cancer models and suppressed in EGFR inhibitor-resistant cells. Prognostic impact was context-dependent: high expression correlated with favorable overall survival in ovarian, lung, and rectum cancers, but inversely with outcomes in liver, breast, and pancreatic cancers. Functionally, p38δ knockdown induced EMT and increased proliferation. Conversely, exogenous p38δ suppressed cell growth/migration. Crucially, acquired Osimertinib resistance consistently corresponded with significant reductions in p38δ levels. CONCLUSION: p38δ is a critical marker and regulator of epithelial identity. Its dysregulation and loss are systematically linked to EMT and drug resistance in cancer. Given its complex, context-dependent prognostic value and functional significance, p38δ holds significant potential as a therapeutic target.