Cytokine and epigenetic regulation of CEACAM6 mediates EGFR-driven signaling and drug response in lung adenocarcinoma
- NPJ Precis Oncol. 2025 Apr 22;9(1):115. doi: 10.1038/s41698-025-00910-z.
- 1. Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.
- 2. Division of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
- 3. Department of Oral Diagnosis & Pathology, Tri-Service General Hospital, Taipei, Taiwan.
- 4. Department of Medicine, National Tsing Hua University, Hsinchu, Institute of Stem Cell and Translational Cancer Research and Department of Anatomic Pathology, Chang Gung Memorial Hospital Linkou, Taoyuan, Taiwan.
- 5. Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan. [email protected].
- # Contributed equally.
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.