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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE330032 | GEO | 2026/05/14

REPOSITORIES: GEO

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Project description:Heatmap, pathway scores and significant modulation of genes induced by heteronemin, tetrac, and their combination versus the control in HCT 116 cells were performed. (abstract) Overexpression of EGFR accounts for 60-80% of colorectal cancer patients. Anti-EGFR monoclonal antibodies are ineffective in colorectal cancer patients due to KRAS mutation. To discover new therapeutic strategies urgently need for colorectal cancer patients. Sponge extract, heteronemin, has been shown to induce anti-proliferation in different types of cancer. Tetrac shows to inhibit Ras-mutant cancer cell proliferation. Cell viability was evaluated in the HT-29 and HCT-116 cell lines to determine the antitumor effects of heteronemin and its combination with tetrac. Gene expressions were determined by NanoString technology and a quantitative RT-PCR. Protein expressions and cell cycle distributions were respectively assessed by Western blotting and flow cytometry. Heteronemin or its combination with tetrac inhibited cancer cell growth in both mutant and KRAS wild-type CRC. Combined treatment altered the cell cycle in both cell lines at the sub-G1 and S phases. Moreover, their combination induced inactivation of EGFR signaling via downregulating the phosphorylated and total extracellular signal-regulated kinase 1/2 (ERK1/2) protein in both cell lines. The programmed death ligand 1 (PD-L1) protein was reduced in HCT-116 cells, while HT-29 cells showed downregulation of the phosphorylated and total phosphatidylinositol 3-kinase (PI3K) protein. In KRAS mutant cells, heteronemin or its combination with tetrac showed significant modulation of genes associated with cancer progression by NanoString technology. Therefore, tetrac improved the anticancer effect of heteronemin and may be an alternative strategy to effective overcome KRAS mutation-acquired resistance to anti-EGFR therapy. 1. To investigate whether heteronemin combined tetrac induce the antitumor effect in different KRAS statuses of CRC via blocking of EGFR signaling cascades. 2. To assess gene expression profiling in KRAS-mutant CRC cells by nanostring technology.

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

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