Triple-Drug Therapy Eliminates Pancreatic Cancer in Mice: A Breakthrough Led by Mariano Barbacid

Pancreatic cancer remains one of the most lethal and treatment-resistant malignancies in modern medicine. Despite decades of research, progress has been slow, largely due to the cancer’s ability to rapidly develop resistance to targeted therapies. Now, a team of scientists in Spain has reported a striking preclinical breakthrough that may change how researchers approach this disease.

Scientists at the Spanish National Cancer Research Center (Centro Nacional de Investigaciones Oncológicas, CNIO), led by renowned cancer geneticist Mariano Barbacid, have demonstrated complete and durable elimination of pancreatic tumours in mice using a carefully designed triple-drug combination.

Complete Tumour Regression in Preclinical Models

The study, published in Proceedings of the National Academy of Sciences, describes how pancreatic tumours disappeared entirely in mouse models and did not return long after treatment ended. Even more remarkably, the therapy was well tolerated, showing minimal toxicity, preserved tissue integrity, stable blood cell counts, and no significant weight loss in the animals.

This is particularly notable because pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is notorious for its ability to evade treatment by activating alternative growth and survival pathways.

Why Pancreatic Cancer Is So Resistant

PDAC is most often driven by KRAS and TP53 mutations and thrives on a dense, protective tumour microenvironment. When one signalling pathway is blocked, tumour cells frequently reroute signals through parallel pathways, leading to rapid drug resistance and treatment failure.

Traditional single-target therapies have therefore shown limited success. Even combination therapies have struggled, as aggressive regimens often prove too toxic to sustain.

The Triple-Target Strategy

Barbacid’s team tackled this challenge by simultaneously blocking three critical signalling nodes involved in pancreatic cancer survival:

• Daraxonrasib (RMC-6236), targeting mutant KRAS signalling
• Afatinib, an EGFR family inhibitor that blocks upstream receptor activation
• SD36, an experimental compound that selectively degrades STAT3, a key survival and inflammation-related pathway

By inhibiting downstream, upstream, and parallel survival signalling at the same time, the therapy effectively left tumour cells without a viable escape route. In orthotopic mouse models, where tumours grow in the pancreas itself, this approach led to complete and lasting tumour regression, with no evidence of resistance for more than 200 days after treatment.

Consistent Results Across Models

To strengthen their findings, the researchers tested the triple therapy across multiple preclinical systems, including genetically engineered mouse models and patient-derived tumour xenografts, where human pancreatic tumours are grown in mice. Across all models, the treatment consistently produced strong tumour regression.

Equally important, the animals tolerated the therapy well, addressing one of the major historical limitations of multi-drug cancer regimens.

Not Ready for Patients Yet

Despite the unprecedented results, the researchers emphasize caution. As Barbacid noted in a CNIO press release, although these outcomes have never been achieved before in pancreatic cancer models, the therapy is not yet ready for human clinical trials. Further studies will be required to refine dosing, safety, and translational feasibility.

Understanding Pancreatic Cancer Risk

Pancreatic cancer is currently the sixth leading cause of cancer-related death worldwide, with a five-year survival rate of around 10%. According to the University of Texas MD Anderson Cancer Center, known risk factors include older age, male sex, smoking, obesity, and African American ethnicity.

The pancreas itself is a vital organ located behind the stomach, responsible for producing digestive enzymes and regulating blood sugar through hormone release. Tumours in this region are often detected late, contributing to poor outcomes.

Who Is Mariano Barbacid?

Mariano Barbacid is one of the most influential figures in modern cancer biology. As head of the Experimental Oncology Group at CNIO, he is best known for isolating the first human oncogene, HRAS, in 1982, a discovery that reshaped cancer genetics. In recognition of his contributions to cancer research and therapy, he was awarded the Echegaray Medal in 2020, Spain’s highest scientific honour.

A Promising Direction for the Future

While these findings remain preclinical, they represent a rare and hopeful advance in pancreatic cancer research. Demonstrating complete, durable tumour regression without resistance challenges long-held assumptions about what is possible in this disease.

If future studies confirm safety and effectiveness in humans, this multi-targeted strategy could open the door to a new generation of pancreatic cancer therapies designed not just to slow the disease, but to outmaneuver it entirely.