The group led by Barbacid in the complete elimination of pancreatic tumors in mice without developing resistance -

Molecular Oncology Group / MadMoviex.

Existing drugs for pancreatic cancer lose their effectiveness within a few months as the tumor becomes resistant.A group from the Spanish National Center for Cancer Research () managed to avoid the development of resistance in animal models with combined triple therapy.

These results "pave the way for the design of combination therapies that can improve quality of life," the authors wrote, although this may not happen in the short term.The results are published in PNAS.

"We are not yet in a position to do clinical trials with this triple therapy," said Mariano Barbacid, head of the experimental oncology group.

In Spain, more than 10,300 cases of pancreatic cancer are diagnosed each year, making it one of the most aggressive forms of cancer.Recognition of the disease at an advanced stage and the lack of effective therapies means that the survival rate five years after diagnosis is less than 10%.But research is finally picking up and starting to shift the paradigm after decades of very limited progress.

Mariano Barbazid, head of the Experimental Oncology Group at the National Cancer Research Center (), has developed a therapy that successfully eradicates pancreatic tumors in mice completely and sustainably, without significant side effects.The study is published in the journal PNAS (Proceedings of the National Academy of Sciences), with Carmen Guerra as lead author and Vasiliki Liak and Sara Barambana as first authors.

"These studies pave the way for the design of new combination therapies that can improve the survival of patients with PDAC [colon carcinoma - the most common type of pancreatic cancer]," the authors said in PNAS."These results set the course for the development of new clinical trials."

Eliminate resistance to treatment.

The first chemotherapy-targeted drugs to treat pancreatic cancer were approved in 2021, after half a century without improvement over conventional chemotherapy.These new drugs block the activity of KRAS, a gene that is mutated in 90% of people with pancreatic cancer.However, their effectiveness is limited because the tumors become resistant to the drugs after a few months.

The issue of resistance to KRAS inhibitor drugs is addressed in a new study by Barbacida, a pioneer in both KRAS research and the development of animal models of pancreatic cancer.

The team's strategy is to block the action of the KRAS oncogene at three points, rather than just one - a beam is harder to break if it is placed on the ceiling at three points, rather than just one.Indeed, after genetically removing three molecules from the KRAS signaling pathway in a mouse model, the tumor disappeared forever.

Focus on three links in a row

Applying the same strategy to patients involves searching for drugs that block the KRAS molecular pathway at the same three points.The team used a triple therapy, combining an experimental KRAS inhibitor (daraxonrasib) with an approved drug for certain lung adenocarcinomas (afatinib) and a protein inhibitor (SD36).

The treatment was applied to three types of pancreatic ductal carcinoma in situ, and in all of them, significant and long-lasting regression of the experimental tumors occurred without significant toxicity, the authors in the PNAS report.

"This study describes a triple combination therapy [...] that induces robust regression of experimental PDACs and prevents the emergence of tumor resistance. This triple combination is well tolerated in mice."

Moving to a clinical trial, but not yet

"Although experimental results like the one described here have not been previously obtained, it is important to understand that we have not yet been able to conduct clinical trials with triple therapy," Barbacid said of the next steps.

The authors emphasize that optimizing triple combination therapy is not easy to apply in the clinical setting."(..) Despite current limitations, these results may open the door to new treatment options in the near future to improve the clinical outcome of patients with pancreatic ductal adenocarcinoma."

This study is supported by Fundación CRIS CONTRA El Cáncer;European Research Council (ERC);State Research Institute, with financial support from the European Regional Development Funds;EUMoney from the next generation;Biomedical networking center (Ciberonc);And Carlos where health institute.

About the National Cancer Research Center ()

National Cancer Research Center () is a public research center under the Ministry of Science, Innovation and Universities.It is the largest cancer research center in Spain and one of the most important centers in Europe.It includes nearly five hundred scientists and support staff working to improve cancer prevention, diagnosis and treatment.

Learn more about pancreatic cancer research:

Liaki V., Barrambana S., Guerra C., Barbacid M. et al, Targeted combination therapy achieves effective regression of pancreatic cancer and prevents tumor resistance, PNAS, December 2025