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<p>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&#xa0;mutant CRC patients possibly allowing to predict therapy responses in patients.</p>

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EGFR controls transcriptional and metabolic rewiring in KRASG12D colorectal cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月6日

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  • Dana Krauß,
  • Veronica 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

摘要

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.