Researchers at the Spanish National Cancer Research Centre (CNIO), led by Dr. Mariano Barbacid, have achieved a significant breakthrough in the treatment of pancreatic ductal adenocarcinoma (PDAC), the most common and deadly form of pancreatic cancer. In a study published in the journal PNAS, the team demonstrated that a new triple-drug combination therapy can completely and permanently eliminate pancreatic tumors in experimental mouse models.
Pancreatic cancer has long been considered one of the most difficult “incurable” diseases, characterized by a five-year survival rate of less than 11%. Its resilience is largely due to the KRAS oncogene, a mutation present in approximately 90% of cases. Although KRAS was historically considered “undruggable,” recent advances have enabled the development of RAS inhibitors. However, these single-target drugs often fail in the long term because tumors quickly develop resistance by utilizing alternative survival pathways.
The CNIO team’s innovation lies in a “triple-threat” approach that blocks three independent signaling nodes simultaneously: downstream (RAF1), upstream (EGFR), and orthogonal (STAT3) pathways. By targeting these three routes, the therapy effectively “traps” the cancer cells, preventing them from outmaneuvering the treatment. The researchers tested this across various models, including mice with human pancreatic tissue and mice genetically engineered to model the disease. In all cases, the combination — consisting of the drugs daraxonrasib (KRAS inhibitor), afatinib (EGFR inhibitor), and SD36 (STAT3 degrader) — resulted in complete tumor regression without the appearance of resistance for over 200 days post-treatment. Crucially, the therapy was well-tolerated with no significant toxicities.
The implications of this study are profound. Currently, patients rely on decades-old cytotoxic drugs like gemcitabine or highly toxic combinations like FOLFIRINOX, which offer limited benefits. This new research provides a roadmap for human clinical trials, suggesting that the key to curing pancreatic cancer lies in combination therapies rather than monotherapy.
While the results are promising, experts note limitations: the success was observed in healthy laboratory mice, and human physiology may present different challenges. Nevertheless, the Spanish government and the international scientific community have hailed the discovery as a potential turning point. If these results can be replicated in humans, it could transform the prognosis for a disease that currently kills more than half of its victims within three months of diagnosis.
.png)
.png)
