Cytokine and epigenetic regulation of CEACAM6 mediates EGFR-driven signaling and drug response in lung adenocarcinoma.

CEACAM family proteins have been extensively studied as cell adhesion molecules, yet the biological and clinical significance of CEACAM6 remains relatively unexplored. Our research identifies a significant increase in CEACAM6 expression in lung adenocarcinoma, particularly correlating with EGFR mutation status. In EGFR-mutated lung cancer cells, CEACAM6 knockdown induced apoptosis and reduced p-ERK1/2 signaling downstream of EGFR. Treatment with EGFR-tyrosine kinase inhibitors (TKIs) decreased CEACAM6 levels, leading to TKI-resistant lung cancer cells that exhibited reduced p-ERK1/2 and increased epithelial-mesenchymal transition (EMT) characteristics. Co-immunoprecipitation assays revealed an interaction between CEACAM6 and EGFR. Although CEACAM6 expression was lost in EGFR-TKI resistant cells, its re-expression stabilized EGFR and increased sensitivity to EGFR-TKIs. TGF-β treatment, which induced EMT, also decreased CEACAM6 expression and improved EGFR-TKI resistance. Further analysis showed that EGFR-TKI resistant lung cancer cells had lower H3K27ac epigenetic modification levels at the CEACAM6 locus than EGFR-TKI sensitive cells. Treatment with HDAC1/2 inhibitors in EGFR-TKI sensitive cells reduced CEACAM6 expression, induced EMT and TGF-β-ligand/receptor gene expression, and enhanced EGFR-TKI resistance. These data highlight the crucial role of CEACAM6 in maintaining oncogenic EGFR signaling and its regulation by cytokine stimulation and epigenetic modification, influencing EGFR-TKI sensitivity. Our findings underscore CEACAM6's potential as a valuable biomarker in EGFR-driven lung adenocarcinoma and its intricate involvement in EGFR-related pathways.