The group led by Barbacid at CNIO completely eliminates pancreatic tumours in mice with no resistance developing
CNIO Molecular Oncology Group/ MadMoviex. CNIO
Current drugs for pancreatic cancer lose effectiveness within months because the tumour becomes resistant. The group from Spain’s National Cancer Research Centre (CNIO) has been able to avoid the development of resistance in animal models with a combined triple therapy.
These results “pave the way for the design of combined therapies that may improve survival,” the authors indicate, although this will not happen in the short term. The results are published in PNAS.
Mariano Barbacid, head of the Experimental Oncology Group at CNIO, emphasises that “we are not yet in a position to carry out clinical trials with this triple therapy.”
In Spain, more than 10,300 cases of pancreatic cancer are diagnosed each year, making it one of the most aggressive forms of cancer. Its detection in the late stages of the disease and the lack of effective therapies mean that the five-year survival rate after diagnosis is less than 10%. But research is finally taking off and starting to change the paradigm after decades of very limited progress.
Mariano Barbacid, head of the Experimental Oncology Group at the National Cancer Research Centre (CNIO), has designed a therapy that successfully eliminates pancreatic tumours in mice completely and durably, with no significant side effects. The study is published in the journal PNAS (Proceedings of the National Academy of Sciences), with Carmen Guerra as co-lead author and Vasiliki Liaki and Sara Barrambana as first authors.
“These studies open the road to design novel combination therapies that may improve the survival of PDAC patients [pancreatic ductal adenocarcinoma – the most common type of pancreatic cancer],” the authors state in PNAS. “These results set the course for developing new clinical trials.”
Eliminating resistance to treatment
The first drugs aiming molecular targets for pancreatic cancer were approved in 2021, after half a century with no improvements over conventional chemotherapy. These new drugs block the action of KRAS, a gene mutated in 90% of people with pancreatic cancer. However, their effectiveness is modest, as the tumour becomes resistant after a few months.
The issue of resistance to KRAS inhibitor drugs is addressed in the new study by Barbacid, a pioneer in both KRAS research and the development of animal models for pancreatic cancer.
The strategy pursued by the CNIO group has been to block the action of the oncogene KRAS at three points, instead of just one – it is harder for a beam to break if it is fixed to the ceiling at three points, rather than just one. And indeed, after genetically eliminating three molecules from the KRAS signalling pathway in mouse models, the tumours disappeared permanently.
Targeting three links in the chain
Applying the same strategy in patients involves searching for drugs that block the KRAS molecular pathway at the same three points. The team employed a triple therapy, which combined an experimental KRAS inhibitor (daraxonrasib) with an approved drug for certain lung adenocarcinomas (afatinib) and a protein degrader (SD36).
The treatment was applied to three mouse models of pancreatic ductal adenocarcinoma, and in all of them, a significant and lasting regression of these experimental tumours was induced without causing significant toxicities, state the authors in PNAS.
“This study describes a triple combination therapy […] that induces the robust regression of experimental PDACs and avoids the onset of tumor resistance. This triple combination is well tolerated in mice.”
Moving towards a clinical trial, but not yet
Regarding the next steps, Barbacid explains: “it is important to understand that, although experimental results like those described here have never been obtained before, we are still not in a position to carry out clinical trials with the triple therapy.”
The authors emphasise that optimising the triple combination therapy for use in a clinical setting will not be easy. “(..) Despite the current limitations, these results could open the door to new therapeutic options to improve the clinical outcome of patients with pancreatic ductal adenocarcinoma in the not too distant future.”
Funding
This study has been funded by Fundación CRIS Contra el Cáncer; the European Research Council (ERC); the State Research Agency, through co-financing with the European Regional Development Fund; Next Generation EU funds; the Biomedical Research Networking Centre (CIBERONC); and the Carlos III Health Institute.
About the National Cancer Research Centre (CNIO)
The National Cancer Research Centre (CNIO) is a public research centre under the Department of Science, Innovation and Universities. It is the largest cancer research centre in Spain and one of the most important in Europe. It includes around five hundred scientists, along with support staff, who are working to improve the prevention, diagnosis and treatment of cancer.
Find out more about pancreatic cancer research:
Reference article
Liaki V., Barrambana S., Guerra C., Barbacid M. et al, A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance, PNAS, Dec. 2025
DOI: https://doi.org/10.1073/pnas.2523039122
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