Targeting the NF-κB pathway represents a potential strategy to attenuate HGF-induced resistance to KRAS G12C inhibitors in lung adenocarcinoma.

Purpose: This study aims to investigate the role of hepatocyte growth factor (HGF) overexpression in mediating resistance to KRAS G12C inhibitors in lung adenocarcinoma and to explore potential combination therapies to attenuate this resistance.

Methods: Lentiviral transfection was used to establish HGF-overexpressing lung adenocarcinoma cell lines harboring the KRAS G12C mutation (H23 and H358). Cells were treated with KRAS G12C inhibitors either as monotherapy or in combination with inhibitors targeting the NF-κB, MEK/ERK, or PI3K/AKT/mTOR pathways. Drug sensitivity was assessed using pharmacological assays, and underlying mechanisms were evaluated through Western blot analysis.

Results: HGF-induced resistance to KRAS G12C inhibitors varied significantly between the two cell lines. H23 cells overexpressing HGF exhibited only mild resistance, which could be reversed using MEK, mTOR, NF-κB, or MET inhibitors. In contrast, H358 cells developed strong resistance following HGF overexpression. Inhibitors of the NF-κB pathway were especially effective in counteracting this resistance, likely by modulating crosstalk among multiple KRAS downstream signaling pathways.

Conclusion: These results indicate that targeting the NF-κB pathway may represent a promising therapeutic strategy to attenuate HGF- induced resistance to KRAS G12C inhibitors in lung adenocarcinoma.