EGFR controls transcriptional and metabolic rewiring in KRASG12D colorectal cancer
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 KRAS<sup>G12D</sup> 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.
Authors
- Jakob‐Wendelin Genger (ORCID: https://orcid.org/0000-0003-4502-1094)
- Dana Krauß (ORCID: https://orcid.org/0000-0002-7310-4340)
- Martin Holcmann (ORCID: https://orcid.org/0000-0003-3362-1359)
- Thomas Mohr (ORCID: https://orcid.org/0000-0002-1933-847X)
- Valeriya Gushchina (ORCID: https://orcid.org/0000-0002-9773-1808)
- Arvand Haschemi (ORCID: https://orcid.org/0000-0001-9532-3205)
- Maria Sibilia (ORCID: https://orcid.org/0000-0001-6129-5613)
- Bernadette Blauensteiner (ORCID: https://orcid.org/0000-0001-6126-3398)
- Ourania Fari (ORCID: https://orcid.org/0000-0003-3988-7684)
- Inbal Mor (ORCID: https://orcid.org/0000-0003-4564-9690)
- Georgios Fotakis (ORCID: https://orcid.org/0000-0001-9659-4226)
- Verónica Moreno‐Viedma (ORCID: https://orcid.org/0000-0003-0906-8725)
- Andreas Bergthaler (ORCID: https://orcid.org/0000-0003-0597-1976)
- Ifat Abramovich (ORCID: https://orcid.org/0009-0009-8760-6630)
- Emi Adachi-Fernandez
- Cristiano De Sá Fernandes (ORCID: https://orcid.org/0000-0002-2863-8458)
- Zlatko Trajanoski (ORCID: https://orcid.org/0000-0002-0636-7351)
- Dominik Kirchhofer
- Juliane Winkler (ORCID: https://orcid.org/0000-0002-9762-1721)
- Eyal Gottlieb (ORCID: https://orcid.org/0000-0002-9770-0956)
- Nikolina Bradaric (ORCID: https://orcid.org/0009-0001-6381-7742)
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Austrian Academy of Sciences (AT)
- Innsbruck Medical University (AT)
- Technion – Israel Institute of Technology (IL)
- Universität Innsbruck (AT)
- Comprehensive Cancer Center Vienna (AT)
- Rappaport Family Institute for Research in the Medical Sciences (IL)
- CeMM Research Center for Molecular Medicine (AT)
- Ariel University (IL)
- Medical University of Vienna (AT)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2025-05-06
- DOI
- https://doi.org/10.1038/s44321-025-00240-4
- Citations
- 3
- Primary Topic
- Colorectal Cancer Treatments and Studies
- Type
- article
- Field-Weighted Citation Impact
- 3.14
Funders
- European Resuscitation Council
- Vienna Science and Technology Fund
- Austrian Science Fund
- Magistrat der Stadt Wien
- HORIZON EUROPE Framework Programme