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Oncogenic KRAS impairs EGFR antibodies' efficiency by C/EBPβ-dependent suppression of EGFR expression
Stefanie Derer1, Sven Berger, Martin Schlaeth
1Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University, Kiel, Germany.
Abstract:
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 KRAS (KRAS(G12V)) impairs effector mechanisms of EGFR-Abs are incompletely understood. Here, we established isogenic cell line models to systematically investigate the impact of KRAS(G12V) on tumor growth in mouse A431 xenograft models as well as on various modes of action triggered by EGFR-Abs in vitro. KRAS(G12V) impaired EGFR-Ab-mediated growth inhibition by stimulating receptor-independent downstream signaling. KRAS(G12V) also rendered tumor cells less responsive to Fc-mediated effector mechanisms of EGFR-Abs-such as complement-dependent cytotoxicity (CDC) and Ab-dependent cell-mediated cytotoxicity (ADCC). Impaired CDC and ADCC activities could be linked to reduced EGFR expression in KRAS-mutated versus wild-type (wt) cells, which was restored by small interfering RNA (siRNA)-mediated knockdown of KRAS4b. Immunohistochemistry experiments also revealed lower EGFR expression in KRAS-mutated versus KRAS-wt harboring CRC samples. Analyses of potential mechanisms by which KRAS(G12V) downregulated EGFR expression demonstrated significantly decreased activity of six distinct transcription factors. Additional experiments suggested the CCAAT/enhancer-binding protein (C/EBP) family to be implicated in the regulation of EGFR promoter activity in KRAS-mutated tumor cells by suppressing EGFR transcription through up-regulation of the inhibitory family member C/EBPβ-LIP. Thus, siRNA-mediated knockdown of C/EBPβ led to enhanced EGFR expression and Ab-mediated cytotoxicity against KRAS-mutated cells. Together, these results demonstrate that KRAS(G12V) signaling induced C/EBPβ-dependent suppression of EGFR expression, thereby impairing Fc-mediated effector mechanisms of EGFR-Abs and rendering KRAS-mutated tumor cells less sensitive to these therapeutic agents.
Insights
Oncogenic KRAS mutations in colorectal cancer reduce the effectiveness of EGFR antibody therapy by decreasing EGFR expression and impairing immune responses like ADCC and CDC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Oncogenic KRAS mutations are common in colorectal cancer (CRC) and are linked to poor response to epidermal growth factor receptor (EGFR)-targeted antibody therapies.
- The precise mechanisms by which KRAS mutations diminish the efficacy of EGFR antibodies remain incompletely understood.
Purpose of the Study:
- To investigate the impact of KRAS(G12V) mutations on tumor growth and the mechanisms of action of EGFR antibodies in colorectal cancer models.
- To elucidate how KRAS(G12V) signaling affects EGFR expression and downstream effector functions of EGFR-directed antibodies.
Main Methods:
- Established isogenic cell line models and A431 xenograft models to study KRAS(G12V) effects.
- Utilized in vitro assays to assess EGFR antibody-mediated growth inhibition, complement-dependent cytotoxicity (CDC), and antibody-dependent cell-mediated cytotoxicity (ADCC).
- Employed siRNA-mediated knockdown of KRAS4b and C/EBPβ, and analyzed transcription factor activity and EGFR promoter activity.
Main Results:
- KRAS(G12V) impaired EGFR antibody-mediated growth inhibition through receptor-independent signaling and reduced responsiveness to CDC and ADCC.
- Reduced EGFR expression was observed in KRAS-mutated cells and CRC samples, which was restored by KRAS4b knockdown.
- KRAS(G12V) suppressed EGFR transcription via C/EBPβ-LIP, leading to decreased EGFR expression and impaired antibody-mediated cytotoxicity.
Conclusions:
- KRAS(G12V) signaling suppresses EGFR expression in a C/EBPβ-dependent manner, diminishing the effectiveness of EGFR antibody therapies in colorectal cancer.
- Targeting C/EBPβ may represent a therapeutic strategy to enhance EGFR antibody efficacy in KRAS-mutated colorectal cancer.
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