Krauß Dana, Moreno-Viedma Veronica, Adachi-Fernandez Emi, de Sá Fernandes Cristiano, Genger Jakob-Wendelin, Fari Ourania, Blauensteiner Bernadette, Kirchhofer Dominik, Bradaric Nikolina, Gushchina Valeriya, Fotakis Georgios, Mohr Thomas, Abramovich Ifat, Mor Inbal, Holcmann Martin, Bergthaler Andreas, Haschemi Arvand, Trajanoski Zlatko, Winkler Juliane, Gottlieb Eyal, Sibilia Maria
Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria.
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, 1090, Austria.
EMBO Mol Med. 2025 May 6. doi: 10.1038/s44321-025-00240-4.
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 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.
表皮生长因子受体（EGFR）的抑制在转移性结直肠癌（CRC）患者中显示出临床益处，但已知KRAS突变会导致耐药。然而，最近的报告强调EGFR是与RAS抑制剂共同抑制以有效治疗KRAS突变型CRC的关键靶点。在此，我们通过建立具有关键CRC突变（KRAS、APC、TP53）和可诱导EGFR缺失的小鼠CRC类器官，研究了EGFR在KRAS肿瘤中的肿瘤细胞内在作用。代谢组学、转录组学和单细胞RNA分析表明，KRAS突变类器官中的EGFR缺失降低了它们的表型异质性，并激活了一种独特的癌症干细胞/WNT特征，这与细胞大小减小以及MAPK、PI3K和ErbB等主要信号级联的下调有关。这伴随着代谢重编程，糖酵解途径减少，回补性谷氨酰胺分解增加。从机制上讲，EGFR缺失后，Smoc2被确定为介导这些表型的关键上调靶点，额外删除Smoc2后这些表型可得到挽救。在患者数据集中的验证表明，所确定的特征与RAS突变型CRC患者更好的总生存期相关，这可能有助于预测患者对治疗的反应。
