Oncogenic KRAS Impairs EGFR Antibodies' Efficiency by C/EBPβ-Dependent Suppression of EGFR Expression

摘要: Oncogenic KRAS mutations in colorectal cancer (CRC) are associated with lack of benefit from epidermal growth factor receptor (EGFR)-directed antibody (Ab) therapy. However, the mechanisms by which constitutively activated (KRASG12V) impairs effector EGFR-Abs incompletely understood. Here, we established isogenic cell line models to systematically investigate impact KRASG12V on tumor mouse A431 xenograft as well various modes action triggered vitro. impaired EGFR-Ab-mediated inhibition stimulating receptor-independent downstream signaling. also rendered cells less responsive Fc-mediated EGFR-Abs—such complement-dependent cytotoxicity (CDC) and Ab-dependent cell-mediated (ADCC). Impaired CDC ADCC activities could be linked reduced EGFR expression KRAS-mutated versus wild-type (wt) cells, was restored small interfering RNA (siRNA)-mediated knockdown KRAS4b. Immunohistochemistry experiments revealed lower KRAS-wt harboring CRC samples. Analyses potential downregulated demonstrated significantly decreased activity six distinct transcription factors. Additional suggested CCAAT/enhancer-binding protein (C/EBP) family implicated regulation promoter suppressing through up-regulation inhibitory member C/EBPβ-LIP. Thus, siRNA-mediated C/EBPβ led enhanced Ab-mediated against cells. Together, these results demonstrate that signaling induced C/EBPβ-dependent suppression expression, thereby impairing rendering sensitive therapeutic agents.