2. Academic Validation
  3. EGFR controls transcriptional and metabolic rewiring in KRASG12D colorectal cancer

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.
Dana Krauß 1,  Veronica Moreno-Viedma 1,  Emi Adachi-Fernandez 1,  Cristiano de Sá Fernandes 1 2,  Jakob-Wendelin Genger 3 2,  Ourania Fari 1,  Bernadette Blauensteiner 1,  Dominik Kirchhofer 1,  Nikolina Bradaric 4,  Valeriya Gushchina 1,  Georgios Fotakis 5,  Thomas Mohr 1,  Ifat Abramovich 6,  Inbal Mor 6 7,  Martin Holcmann 1,  Andreas Bergthaler 3 2,  Arvand Haschemi 4,  Zlatko Trajanoski 5,  Juliane Winkler 1,  Eyal Gottlieb 6 8,  Maria Sibilia 9
Affiliations

Affiliations

  • 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. Maria.Sibilia@meduniwien.ac.at.
PMID: 40329096 DOI: 10.1038/s44321-025-00240-4
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

CRC-organoids; EGFR; KRAS; Metabolism; Stemness-WNT.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-134813
    99.97%, KRAS G12D抑制剂
    Ras
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