KRAS is one of the most frequently altered oncogenes in cancer, being mutated in approximately one-third of lung adenocarcinomas. For decades, it was thought to be untreatable until recently, when the first inhibitor against a specific KRAS variant was approved. However, these treatments often lose effectiveness over time due to the development of resistance. This new study now explores a different pharmacological strategy based on inducing tumor cells to degrade mutant KRAS themselves.
The study, led by IRB Barcelona and Centro de Investigación del Cáncer (CSIC, USAL, FICUS), demonstrated that disrupting the mutant KRAS protein, rather than simply inhibiting its activity, induced greater lung cancer regression in a preclinical mouse model.
Published in cancer researchthis study also provides one of the first in vivo characterizations of how tumors acquire resistance to targeted proteolytic therapy based on PROTAC, a new therapy that has already reached clinical approval.
KRAS inhibitors have revolutionized the treatment of certain cancers, but resistance remains a major hurdle. We are now entering a new era in which we can not only inhibit KRAS but also induce its degradation within cancer cells. Combining both pharmacological strategies sequentially or simultaneously can make a big difference. ”
Dr. Cristina Mayor Ruiz, researcher at the Barcelona IRB and co-lead author of the study
Induction of KRAS degradation in tumor cells
Unlike classical inhibitors, which block protein activity, targeted proteolysis strategies utilize molecules known as PROTACs to force cells to destroy tumor proteins themselves.
Since PROTACs that can directly degrade the KRASG12V mutation are not currently available, the researchers devised an ingenious strategy. This involves adding a “molecular tag” to the protein. This allowed them to force its disassembly using a new PROTAC specifically concerned with this tag, designed and synthesized at the Barcelona IRB in collaboration with Antoni Riera’s group.
Using this approach, the researchers were able to successfully degrade KRASG12V in vivo and observed significant tumor regression. This newly developed model has not only proven useful for studying lung cancer, but also provides a framework to study targeted proteolytic therapies against other cancer-associated proteins and tumor types.
What we are observing is that lung cancer cells are highly dependent on mutant KRAS. Degrading the mutated protein stops proliferation and causes apoptosis, even in the absence of a functioning immune system. ”
Dr. David Santamaria, Cancer Research Center researcher and co-lead author of the study
Although treated tumors show increased immune cell infiltration, experiments performed in immunodeficient mice demonstrated that early regression depends primarily on cancer cell-specific mechanisms rather than immune system activity.
The results further demonstrate that targeted KRASG12V degradation elicits deeper and more durable antitumor responses than those observed with conventional inhibitors.
Research on resistance to decomposed substances in vivo
One of the most important findings of this study was the detailed analysis of how resistance to targeted proteolytic therapy manifests in living tumors. The researchers observed that these resistance mechanisms are different from those previously described for traditional inhibitors.
Instead of mutating KRAS or reactivating classical oncogenic signaling pathways in response to degradation factors, cancer cells gradually alter the cellular machinery involved in protein removal, thereby preventing KRAS from being effectively degraded.
“This is a fundamentally different resistance mechanism. The tumor continues to rely on KRAS, but essentially learns to thwart the mechanisms that are meant to destroy the tumor,” notes Inés M. García Pérez, co-lead author of the study and a postdoctoral fellow at the Barcelona Institutional Review Board.
This research resulted from a collaboration between a group led by Drs. Dr. Cristina Mayor Ruiz of the Barcelona IRB; David Santamaria of the Center for Cancer Research (CSIC, USAL, FICUS); The study also includes important contributions from researchers at the University of Salamanca, the University of Navarra, the Catalunya Oncology Institute, the University of Liege, the University of Turin, CIBERONC and the University of Barcelona.
This research was supported by funding from the Spanish Ministry of Science and Innovation (National Program for Scientific and Technological Research and Innovation), the European Research Council (ERC), the Spanish Association Against Cancer (AECC), the Autonomous Region of Catalonia (AGAUR and TRIP-Clinics), the European Union’s NextGenerationEU program, the “la Caixa” Foundation, and Farmaindustria.
sauce:
Institute of Biomedical Research (IRB Barcelona)
Reference magazines:
Martin, A. and others. (2026). Targeted KRASG12V degradation in vivo induces lung adenocarcinoma regression followed by relapse from dysregulated protein degradation. cancer research. DOI: 10.1158/0008-5472.can-25-5172. https://aacrjournals.org/cancerres/article-abstract/doi/10.1158/0008-5472.CAN-25-5172/785288/Targeted-KRASG12V-Degradation-in-vivo-Elicits-Lung?redirectedFrom=fulltext
