EGFR controls transcriptional and metabolic rewiring in KRASG12D colorectal cancer
Dana Krauß, Verónica Moreno‐Viedma, Emi Adachi-Fernandez, Cristiano De Sá Fernandes, Jakob‐Wendelin Genger, Ourania Fari, Bernadette Blauensteiner, Dominik Kirchhofer, Nikolina Bradaric, Valeriya Gushchina, Georgios Fotakis, Thomas Mohr, Ifat Abramovich, Inbal Mor, Martin Holcmann, Andreas Bergthaler, Arvand Haschemi, Zlatko Trajanoski, Juliane Winkler, Eyal Gottlieb, Maria Sibilia
Abstract
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 KRAS G12D 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.