KRAS mutations are among the many commonest genetic alterations in most cancers and are thought-about notably troublesome to deal with. In colon most cancers, the second commonest explanation for most cancers demise, such mutations severely restrict therapeutic choices.
The outcomes of a research led by the Heart for Most cancers Analysis on the Medical College of Vienna, lately printed within the journal EMBO Molecular Medication, now elevate a beforehand little-considered technique: the focused blockade of the EGFR signaling pathway—even within the presence of a KRAS mutation. This might make KRAS-mutated colon most cancers extra treatable than beforehand thought.
“Our outcomes present that EGFR, a receptor on the cell floor of many cells, additionally performs an lively position in KRAS-mutated colorectal tumors—and another way than beforehand thought,” explains first writer Dana Krauß (Heart for Most cancers Analysis on the Medical College of Vienna and Complete Most cancers Heart Vienna of MedUni Vienna and College Hospital Vienna).
“This discovering contradicts the long-held assumption that this receptor has no therapeutic relevance in tumors with a KRAS mutation.”
Utilizing so-called tumor organoids—mini-tumors produced from colon most cancers cells remoted from particular mouse fashions—the analysis group was capable of reveal that the removing of EGFR has a profound impact on the metabolism of most cancers cells.
The cells processed sugar and amino acids in a very completely different method—a sign of recent vulnerabilities in KRAS-mutated tumors. As well as, EGFR blockade activated a selected gene signature related to longer survival of colorectal most cancers (CRC) sufferers with KRAS mutations.
Gene may play a key position
EGFR was beforehand thought-about an ineffective therapeutic goal in KRAS-mutated tumors. Nonetheless, metabolic analyses have now proven that EGFR blockade in colorectal organoids slows down sugar metabolism (glycolysis) and causes tumor cells to change to glutamine as an alternative—a elementary change in cell metabolism.
On the similar time, key development signaling pathways have been considerably weakened. Additionally shocking was the noticed discount in cell measurement and the activation of stem cell signatures and the Wnt signaling pathway identified to be concerned in CRC growth—a sign that the tumor cells reply to EGFR blockade with an alternate developmental program.
The Smoc2 gene was found to play a key position in these processes: it’s answerable for rewiring the cell metabolism and for activating new signaling networks. By analyzing in depth affected person knowledge units, the researchers have been additionally capable of present that the recognized gene signature is related to higher survival in sufferers with KRAS-mutated CRC.
Present apply referred to as into query
These findings present a mechanistic clarification for why EGFR additionally performs a task in KRAS-mutated tumors—and name into query the present apply of excluding such sufferers from EGFR-targeted therapies. On the similar time, they strengthen the method of creating mixture therapies that block each EGFR and KRAS sooner or later. Though medical trials are nonetheless pending, the info present that KRAS-mutated CRC could also be extra treatable than beforehand thought.
“This analysis reveals how vital it’s to critically query assumptions—particularly in ailments for which there are at present few efficient therapies,” emphasizes research chief Maria Sibilia, Head of the Heart for Most cancers Analysis at MedUni Vienna.
Extra info:
Dana Krauß et al, EGFR controls transcriptional and metabolic rewiring in KRASG12D colorectal most cancers, EMBO Molecular Medication (2025). DOI: 10.1038/s44321-025-00240-4
Quotation:
Missed technique reveals promise for treating KRAS-mutated colon most cancers (2025, Might 26)
retrieved 26 Might 2025
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