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

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.