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Dr. Eduard Batlle (IRB Barcelona), Dr. Marc Martí-Renom, and Dr. Carme Cortina with the rest of the research team. Photo / IRB Barcelona
 27.10.2025

IRB Barcelona discovers why some colorectal cancers are resistant to the pharmacological inhibition of the KRAS oncogene

A new study by the Institute for Biomedical Research of Barcelona (IRB Barcelona), based at the Barcelona Science Park, reveals why in colorectal cancer with the KRAS oncogene mutation, treatment pressure can redirect cellular states instead of simply eliminating them. Addressing heterogeneity and plasticity—particularly the emergence of the LGR5 state—could be essential to improve therapeutic outcomes. The research, published in the journal Cancer Discovery, was conducted by IRB Barcelona, together with the National Centre for Genomic Analysis (CNAG) and in collaboration with Revolution Medicines.

The research led by Dr. Eduard Batlle (ICREA researcher at IRB Barcelona and CIBERONC investigator) and Dr. Carme Cortina (IRB Barcelona), together with Dr. Marc Martí-Renom (CNAG), shows that metastatic colorectal cancers (mCRCs) exist in multiple cellular states and exhibit distinctive properties. Within a single tumor, cells can rapidly switch from one state to another, a key feature of cancer known as transcriptional plasticity. This flexibility allows mCRCs with KRAS mutations to resist treatment with a new targeted compound that selectively inhibits oncogenic KRAS signaling.

Using preclinical models of mCRC, the authors show that oncogenic KRAS induces a cell state associated with metastasis and poor prognosis. However, when mutant KRAS activity is blocked with a KRAS mutant-selective inhibitor, tumor cells switch from this state to a stem-like state marked by LGR5. These LGR5⁺ cells depend less on KRAS signaling, which may explain the limited benefit of KRAS-targeted approaches in colorectal cancer.

The team finds that this switch is driven by changes in gene-reading programs that control which genes are turned on or off and define cell identity, rather than by new DNA mutations—highlighting plasticity as the main escape route.

In preclinical models of colorectal cancer metastasis, combining KRAS-pathway inhibition with strategies that eliminate the emergent LGR5⁺ population produced stronger, longer-lasting responses.

The study also involved researchers from VHIO (Barcelona), the Research Institute of Molecular Pathology (IMP, Vienna), CIBERONC, Imperial College (London), the Francis Crick Institute (London), CSIC’s Instituto de Investigaciones Biomédicas Sols-Morreale (Madrid) and IdiPAZ (Madrid).

» Related article:  A plastic EMP1⁺ to LGR5⁺ cell state conversion as a therapeutic bypass to KRAS-G12D inhibition in metastatic colorectal cancer. Centonze A, Roura AJ, Novillo-Font M, Giordano C, Hernando-Momblona X, Llanses M, Prats P, Sevillano M, Cabot D, Novell M, Pabst G, Andersch F, Cañellas-Socias A, Zhang C, Giakoumakis NN, Sparks H, Dunsby C, Colombelli J, Fernández-Barral A, Sancho E, Stephan-Otto Attolini C, Muñoz A, Barbachano A, Palmer HG, Martínez-Quintanilla J, Zuber J, Blaj C, Quintana E, Cortina C, Marti-Renom MA, Batlle E. A plastic EMP1⁺ to LGR5⁺ cell state conversion as a bypass to KRAS-G12D pharmacological inhibition in metastatic colorectal cancer. Cancer Discov. 2025 Oct 21. doi: 10.1158/2159-8290.CD-25-0679. Epub ahead of print. PMID: 41128661.

» Link to the news: IRB Barcelona website [+]