Subtype-specific heterogeneity of anti-epidermal growth factor receptor antibody sensitivity in KRAS-mutant colorectal cancer revealed by patient-derived organoids

Anti–epidermal growth factor receptor (anti-EGFR) antibodies are widely used in the treatment of colorectal cancer (CRC), and KRAS mutation status is commonly used as a predictive biomarker for therapeutic responsiveness. Nevertheless, emerging evidence suggests that drug sensitivity among KRAS-mutant CRC is heterogeneous and varies according to mutation subtype. In this study, we reevaluated the determinants of anti-EGFR antibody sensitivity using a patient-derived CRC organoid library. Eight organoid lines comprising KRAS wild-type, KRAS G12-mutant, and KRAS G13-mutant tumors were subjected to drug sensitivity assays. Although KRAS G12-mutant organoids generally exhibited reduced responsiveness to anti-EGFR antibodies, KRAS G13-mutant organoids demonstrated sensitivity comparable to that of KRAS wild-type organoids. Transcriptomic analysis of a KRAS G13-mutant organoid after anti-EGFR antibody treatment revealed significant alterations in gene expression, with enrichment of MYC-related signaling pathways. These results were supported by in silico analyses using public cancer cell line datasets, which showed relatively lower IC50 values for KRAS G13-mutant cells than for KRAS G12-mutant cells. Moreover, anti-EGFR antibody treatment induced the expression of apoptosis-related genes in KRAS G13-mutant organoids, and pharmacological inhibition of MYC signaling attenuated drug sensitivity, indicating a functional role for MYC activation in mediating therapeutic response. Altogether, our results demonstrate heterogeneity in anti-EGFR antibody sensitivity among KRAS-mutant CRCs and identify KRAS G13-mutant tumors as a subset with preserved responsiveness. These data provide mechanistic insights into subtype-specific differences in therapeutic vulnerability and suggest that downstream transcriptional programs, including MYC signaling, contribute to sensitivity to EGFR-targeted therapy.