Abstract 1886: Ligand links EGFR reactivation to resistance against KRAS G12C inhibitors in NSCLC.

Abstract KRAS G12C inhibitors have shown meaningful clinical efficacy against Kirsten rat sarcoma viral oncogene (KRAS) G12C-mutant non-small cell lung cancer (NSCLC), providing a long-awaited therapeutic option for this historically difficult-to-target oncogene. However, both intrinsic and acquired resistance frequently limit the durability of response. To overcome these limitations, rational combination strategies based on molecular mechanisms are urgently needed. Although multiple combination approaches—such as co-targeting EGFR or PD-L1—are being evaluated in ongoing trials, biomarker-driven therapeutic selection remains underdeveloped. To elucidate the mechanisms underlying resistance, we established intrinsic and acquired KRAS G12C inhibitor-resistant tumor models using mouse and patient-derived xenografts (PDX). Mechanistic analyses, including western blotting and enzyme-linked immunosorbent assay (ELISA), were conducted to characterize resistance-associated signaling. Combination treatment efficacy was validated in vitro and in vivo. In addition, immunohistochemistry (IHC) and RNAscope in situ hybridization (ISH) were performed on xenograft tissues and tumor samples from patients with KRAS G12C-mutant NSCLC treated with sotorasib. Our findings reveal that tumor cell-autocrine ligand-mediated epidermal growth factor receptor (EGFR) phosphorylation plays a central role in both intrinsic and acquired resistance to KRAS inhibitors. Strikingly, this same EGFR signaling axis was also detected in central nervous system (CNS) metastatic recurrence in a leptomeningeal carcinomatosis model, indicating its relevance to disease progression in sanctuary sites. Moreover, RNAscope ISH enabled spatial visualization of ligand expression, suggesting its potential as a diagnostic marker for identifying patients with EGFR-dependent resistance. Importantly, combined inhibition of KRAS and EGFR effectively suppressed tumor growth and overcame resistance in vitro and in vivo. Consistent with these preclinical results, elevated EGFR ligand mRNA expression was observed in two of seven clinical tumor samples from patients with KRAS G12C-mutant NSCLC who exhibited poor response to sotorasib. In conclusion, ligand-mediated EGFR activation serves as a key driver of both intrinsic and acquired resistance to KRAS G12C inhibitors in NSCLC. These results establish a mechanistic rationale for biomarker-guided combination therapy using concurrent KRAS and EGFR inhibition to enhance therapeutic efficacy and prevent resistance in KRAS G12C-mutant lung cancer. Citation Format: Shigeki Nanjo, Yifeng Liu, Hayato Koba, Seiji Yano. Ligand links EGFR reactivation to resistance against KRAS G12C inhibitors in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1886.