Dual targeting of CEACAM6 and EGFR with a bispecific antibody induces EGFR degradation and overcomes anti-EGFR resistance

Epidermal growth factor receptor (EGFR) protein stability is an important determinant of tumor progression and therapeutic response. Here, we identified carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) as a previously unrecognized post-translational stabilizer of EGFR. CEACAM6 expression positively correlated with EGFR protein, but not mRNA, in clinical specimens. Mechanistically, CEACAM6 sequesters EGFR into CEACAM6-enriched lipid rafts, which delays the raft-associated endocytosis and lysosomal degradation of EGFR. This retention maintains EGFR clustering and sustains downstream ERK, AKT, and SRC signaling, promoting migration, invasion, and anoikis resistance, ultimately contributing to resistance against anti-EGFR therapeutics. To therapeutically exploit this vulnerability, we developed an anti-CEACAM6/EGFR bispecific antibody (BsAb) that simultaneously engages both antigens on the tumor cell surface. The BsAb induces potent antigen crosslinking that triggers efficient EGFR internalization and redirects it toward lysosomal degradation, thereby bypassing the CEACAM6-dependent blockade of EGFR turnover. In addition, the BsAb efficiently suppressed the progression and metastasis of colorectal and lung cancer in xenograft models. These findings identify CEACAM6 as a critical regulator of EGFR stability and demonstrate that dual targeting with the bispecific antibody can induce EGFR degradation, thereby overcoming EGFR-driven malignancy.