EGFR inhibition alters metabolism in KRAS-mutant colon cancer

A new study [1] from the Medical University of Vienna has uncovered a surprising vulnerability in colorectal cancers driven by KRAS mutations - one of the most common and notoriously treatment-resistant alterations in cancer. Published in EMBO Molecular Medicine, the findings suggest that blocking EGFR, a receptor long thought irrelevant in KRAS-mutant tumours, could significantly impair tumour metabolism and improve patient outcomes.

The research team, led by Professor Maria Sibilia at the Center for Cancer Research, used colorectal cancer organoids - miniature tumour models grown from mouse-derived cancer cells - to show that genetic deletion of EGFR altered how the cells process nutrients. Specifically, EGFR loss shifted metabolism from glycolysis towards glutamine use, while suppressing key growth signals and triggering gene expression changes linked to longer survival in patients.

“This contradicts the prevailing belief that EGFR has no therapeutic value in KRAS-mutated tumours,” said first author Dana Krauß. “We found that EGFR remains functionally important and creates metabolic dependencies that could be exploited.”

One gene in particular, Smoc2, was identified as a critical regulator of the tumour’s metabolic reprogramming following EGFR loss. The team also observed that EGFR-deficient tumours activated alternative developmental pathways - including stem cell signatures and Wnt signalling - suggesting a complex adaptive response with potential druggable nodes.

The results raise fresh questions about current treatment strategies that exclude patients with KRAS mutations from EGFR-targeted therapies. They also open the door to combination treatments targeting both KRAS and EGFR.

“These findings provide a molecular rationale for re-evaluating EGFR inhibition in KRAS-mutant colorectal cancer,” said Professor Maria Sibilia, Head of the Center for Cancer Research at the Medical University of Vienna. “It’s a reminder of the value of re-examining established dogmas in cancer biology.”

More information online

1. Krauß, D. et al. EGFR controls transcriptional and metabolic rewiring in KRASG12D colorectal cancer published in EMBO Molecular Medicine (2025)