Mariano Barbacid’s Team Achieves Complete Pancreatic Tumor Elimination in Mice

The Oncology Molecular Group at the Spanish National Cancer Research Centre (CNIO), led by Mariano Barbacid, has achieved a remarkable breakthrough in pancreatic cancer research. Their innovative triple therapy has demonstrated the complete elimination of tumors in mice, crucially, without the development of drug resistance. This research, published in PNAS, offers a promising new avenue for developing more effective treatments for this aggressive disease.

The Challenge of Pancreatic Cancer

Pancreatic cancer is notoriously difficult to treat. Current drugs often lose effectiveness within months as the tumor develops resistance. In Spain alone, over 10,300 cases are diagnosed annually, and the five-year survival rate remains below 10% due to late detection and limited treatment options. However, recent advancements are beginning to shift the paradigm after decades of slow progress.

A Novel Triple Therapy Approach

Mariano Barbacid, head of the CNIO’s Experimental Oncology Group, has spearheaded the development of a therapy that completely and durably eliminates pancreatic tumors in mice, with minimal side effects. The study, co-authored by Carmen Guerra, Vasiliki Liaki, and Sara Barrambana, suggests a path towards designing new combination therapies to improve patient survival rates.

Overcoming Treatment Resistance

Recent advancements in targeted therapies for pancreatic cancer, approved in 2021, focused on blocking KRAS, a gene mutated in 90% of pancreatic cancer cases. However, tumors quickly develop resistance to these drugs. Barbacid’s team addressed this issue by simultaneously blocking KRAS action at three different points, making it significantly harder for the tumor to evade treatment – a strategy akin to securing a beam to the ceiling with three anchors instead of one.

By genetically eliminating three molecules within the KRAS signaling pathway in mouse models, the team achieved permanent tumor regression.

The Triple Combination

To translate this strategy to patients, the researchers combined three drugs: daraxonrasib (a KRAS inhibitor for experimental use), afatinib (approved for certain lung adenocarcinomas), and SD36 (a protein degrader). Applied to three mouse models of pancreatic ductal adenocarcinoma, the triple therapy induced “significant and durable regression” of tumors without causing significant toxicity.

As the authors state in PNAS, this combination “induces the robust regression of experimental models of pancreatic ductal adenocarcinoma, and prevents the emergence of resistances.”

Looking Ahead: Clinical Trials on the Horizon

While these results are incredibly promising, Barbacid cautions that clinical trials are not yet imminent. “It’s important to understand that, while we’ve never obtained experimental results like these before, we are not yet in a position to conduct clinical trials with the triple therapy,” he explains. Optimizing the therapy for clinical use will be a complex process.

Despite these challenges, the research offers a beacon of hope for future therapeutic options and improved clinical outcomes for patients with pancreatic ductal adenocarcinoma.

Funding

This study was funded by the CRIS Cancer Foundation, the European Research Council (ERC), the State Research Agency in co-financing with the European Regional Development Fund, Next Generation funds from the European Union, the Biomedical Research Centre Network (CIBERONC), and the Carlos III Health Institute.

About the Spanish National Cancer Research Centre (CNIO)

The CNIO is Spain’s leading cancer research center and a major player in Europe. It employs over 500 scientists dedicated to improving cancer prevention, diagnosis, and treatment.

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