EGFR controls transcriptional and metabolic rewiring in KRASG12D colorectal cancer
- EMBO Mol Med. 2025 Jun;17(6):1355-1392. doi: 10.1038/s44321-025-00240-4.
- 1. Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria.
- 2. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, 1090, Austria.
- 3. Institute of Hygiene and Applied Immunology, Department of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, 1090, Austria.
- 4. Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria.
- 5. Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria.
- 6. Department of Cell Biology and Cancer Science, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
- 7. Department of Molecular Biology, Ariel University, Ariel, 4070000, Israel.
- 8. Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- 9. Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria. [email protected].
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.