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KRAS mutations are among the many commonest genetic alterations in most cancers and are thought of notably troublesome to deal with. In colon most cancers, the second commonest reason for most cancers demise, such mutations severely restrict therapeutic choices.
The outcomes of a examine led by the Heart for Most cancers Analysis on the Medical College of Vienna, lately revealed within the journal EMBO Molecular Medication, now increase 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 results show that EGFR, a receptor on the cell surface of many cells, also plays an active role in KRAS-mutated colorectal tumors—and in a different way than previously 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 finding 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 constituted of colon most cancers cells remoted from particular mouse fashions—the analysis crew was capable of show that the elimination of EGFR has a profound impact on the metabolism of most cancers cells.
The cells processed sugar and amino acids in a totally totally different manner—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 might play a key function
EGFR was beforehand thought of 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 modify to glutamine as an alternative—a basic change in cell metabolism.
On the similar time, key progress 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 recognized to be concerned in CRC improvement—a sign that the tumor cells reply to EGFR blockade with another developmental program.
The Smoc2 gene was found to play a key function in these processes: it’s accountable 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 observe referred to as into query
These findings present a mechanistic clarification for why EGFR additionally performs a job in KRAS-mutated tumors—and name into query the present observe of excluding such sufferers from EGFR-targeted therapies. On the similar time, they strengthen the strategy of growing mixture therapies that block each EGFR and KRAS sooner or later. Though scientific trials are nonetheless pending, the information present that KRAS-mutated CRC could also be extra treatable than beforehand thought.
“This research shows how important it is to critically question assumptions—especially in diseases for which there are currently few effective therapies,” emphasizes examine 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
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Medical College of Vienna
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Neglected technique reveals promise for treating KRAS-mutated colon most cancers (2025, Could 26)
retrieved 26 Could 2025
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