CEACAM家族蛋白是已知的細胞黏附分子，但其中CEACAM6在肺腺癌（LUAD）中的生物學與臨床意義仍未被充分探討。本研究指出，CEACAM6是LUAD中表現量最高的CEACAM家族成員之一，且其表現高度集中於EGFR突變的腫瘤中。在功能層面，CEACAM6透過與EGFR互相作用，促進EGFR蛋白的穩定性，並維持ERK1/2的磷酸化，從而支持腫瘤促進的訊號傳導。在EGFR突變的LUAD細胞中抑制CEACAM6，會誘導細胞凋亡、降低p-ERK1/2的表現，並抑制細胞增殖。相反地，在EGFR-TKI抗藥性的細胞中重新表達CEACAM6，可恢復EGFR訊號並使細胞重新對gefitinib產生敏感性。在TKI抗藥性模型中，CEACAM6表現普遍下調，伴隨p-ERK1/2的下降及上皮-間質轉化（EMT）特徵的出現。機制上，CEACAM6的下調是由TGF-β訊號透過SMAD依賴性途徑所驅動，同時也涉及表觀遺傳重編程，包括H3K27ac的減少與HDAC介導的抑制。在TKI敏感的細胞中抑制HDAC1/2會降低CEACAM6表現、活化EMT與TGF-β相關基因，並引起對TKI的抗性。總結而言，本研究確立CEACAM6在EGFR–ERK訊號傳導、EMT及治療反應中的關鍵調節角色，並突顯其作為肺腺癌中EGFR依賴性與抗藥性相關生物標誌的潛力。

CEACAM family proteins are well-characterized cell adhesion molecules, yet the biological and clinical significance of CEACAM6 in lung adenocarcinoma (LUAD) remains underexplored. Here, we identify CEACAM6 as one of the most highly expressed CEACAM family members in LUAD, with its expression strongly enriched in EGFR-mutant tumors. At the functional level, CEACAM6 supports oncogenic signaling by interacting with EGFR, enhancing its protein stability, and sustaining ERK1/2 phosphorylation. Silencing CEACAM6 in EGFR-mutant LUAD cells induces apoptosis, reduces p-ERK1/2 levels, and suppresses cell proliferation. Conversely, re-expression of CEACAM6 in EGFR-TKI–resistant cells restores EGFR signaling and re-sensitizes cells to gefitinib. In TKI-resistant models, CEACAM6 expression is consistently downregulated and accompanied by reduced p-ERK1/2 levels and the emergence of epithelial–mesenchymal transition (EMT) traits. Mechanistically, CEACAM6 suppression is driven by TGF-β signaling through a SMAD-dependent pathway, as well as by epigenetic reprogramming, including reduced H3K27ac enrichment and histone deacetylase (HDAC)-mediated repression. HDAC1/2 inhibition in TKI-sensitive cells decreases CEACAM6 levels, activates EMT and TGF-β–related genes, and induces TKI resistance. Collectively, these findings establish CEACAM6 as a pivotal modulator of EGFR–ERK signaling, EMT, and therapeutic response in LUAD, and highlight its potential utility as a biomarker for EGFR pathway dependency and resistance in lung adenocarcinoma.