Faculty, Staff and Student Publications

Publication Date

6-1-2025

Journal

EMBO Molecular Medicine

DOI

10.1038/s44321-025-00240-4

PMID

40329096

PMCID

PMC12162862

PubMedCentral® Posted Date

5-6-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Inhibition of the epidermal growth factor receptor (EGFR) shows clinical benefit in metastatic colorectal cancer (CRC) patients, but KRAS-mutations are known to confer resistance. However, recent reports highlight EGFR as a crucial target to be co-inhibited with RAS inhibitors for effective treatment of KRAS mutant CRC. Here, we investigated the tumor cell-intrinsic contribution of EGFR in KRASG12D tumors by establishing murine CRC organoids with key CRC mutations (KRAS, APC, TP53) and inducible EGFR deletion. Metabolomic, transcriptomic, and scRNA-analyses revealed that EGFR deletion in KRAS-mutant organoids reduced their phenotypic heterogeneity and activated a distinct cancer-stem-cell/WNT signature associated with reduced cell size and downregulation of major signaling cascades like MAPK, PI3K, and ErbB. This was accompanied by metabolic rewiring with a decrease in glycolytic routing and increased anaplerotic glutaminolysis. Mechanistically, following EGFR loss, Smoc2 was identified as a key upregulated target mediating these phenotypes that could be rescued upon additional Smoc2 deletion. Validation in patient-datasets revealed that the identified signature is associated with better overall survival of RAS mutant CRC patients possibly allowing to predict therapy responses in patients.

Keywords

Colorectal Neoplasms, ErbB Receptors, Animals, Proto-Oncogene Proteins p21(ras), Humans, Mice, Organoids, Mutation, Gene Expression Regulation, Neoplastic, EGFR, KRAS, CRC-organoids, Metabolism, Stemness-WNT, Cancer, Chromatin, Transcription & Genomics, Digestive System

Published Open-Access

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