For decades, pancreatic cancer has defied the best efforts of modern medicine. With a five-year survival rate hovering at just 13 percent and the disease currently ranking as the third leading cause of cancer death in the United States, any meaningful advance against this malignancy carries profound weight. Now, researchers at the Spanish National Cancer Research Centre have achieved something unprecedented: the complete and permanent elimination of pancreatic tumors in mouse models using a carefully orchestrated combination of three drugs that attack the cancer from multiple angles simultaneously.

The study, published in the Proceedings of the National Academy of Sciences, represents the culmination of more than four decades of work by Mariano Barbacid, who first identified the KRAS oncogene in 1982. This gene, when mutated, functions like a stuck accelerator pedal, constantly signaling cells to divide and proliferate. It drives roughly 90 percent of all pancreatic ductal adenocarcinomas, the most common and lethal form of the disease.

“These studies open a path to designing new combination therapies that can improve survival for patients with pancreatic ductal adenocarcinoma,” the authors state in their paper. “These results point the way for developing new clinical trials.”

The ‘Undruggable’ Target

The history of attempting to block KRAS reads like a chronicle of frustration. For nearly forty years after Barbacid’s discovery, scientists struggled to find a chemical way to inhibit the protein. Its structure offered no obvious binding pocket where a drug might attach, and its extraordinarily tight grip on the energy molecule GTP made competitive inhibition essentially impossible. The oncogene earned a grim reputation as “undruggable.”

The first breakthrough came in 2021, when drugs called sotorasib and adagrasib received approval for treating certain lung cancers. These medications target a specific mutation called G12C, which occurs in about 13 percent of non-small cell lung cancers but appears in only 1 to 2 percent of pancreatic tumors. While the approvals represented a conceptual victory, they offered little practical benefit to pancreatic cancer patients, most of whom carry different mutations, particularly G12D, found in roughly 45 percent of cases.

“KRAS inhibitors have transformed the landscape of cancer treatment, although their efficacy is currently limited and the emergence of resistance is almost inevitable,” explains Elena Zamorano, a researcher in Barbacid’s Experimental Oncology Group.

The Resistance Problem

Even when KRAS-targeting drugs do work initially, pancreatic tumors have an unsettling ability to adapt. Block one pathway, and the cancer often activates alternative molecular escape routes, resuming its relentless growth within months. This resistance pattern explains why single-drug approaches have consistently disappointed in clinical settings.

Second-generation KRAS inhibitors like daraxonrasib have shown promise in early trials, extending average survival from roughly six to seven months to fourteen months in pancreatic cancer patients. While these results are considered encouraging, they underscore the persistent challenge of resistance.

Barbacid’s team approached this problem with a simple but powerful analogy: a beam fixed to a ceiling at three points is far harder to break than one attached at only one. Rather than blocking a single molecular target, they designed a strategy to simultaneously disable three critical nodes in the cancer’s survival machinery.

The Triple Combination

The therapy combines daraxonrasib, which directly inhibits multiple KRAS mutations; afatinib, an already-approved drug that blocks the EGFR family of receptors often used as escape routes by tumors; and SD36, an experimental compound that degrades the STAT3 protein involved in tumor cell survival and stress responses. In essence, the treatment cuts the engine, seals the exits, and disables the emergency backup system.

The researchers tested this combination in three different mouse models of pancreatic ductal adenocarcinoma. In mice with implanted tumor cells, the triple therapy induced complete and lasting regression with no evidence of tumor resistance for more than 200 days after treatment. Analysis of their pancreatic tissue revealed no tumor remnants whatsoever.

In genetically engineered mice designed to more closely mimic human disease, nine of twelve animals achieved complete regression and remained disease-free for at least 100 days without relapse. By comparison, mice receiving daraxonrasib alone showed doubled survival but none survived treatment long-term.

“This study describes a triple combination therapy that induces robust regression in experimental models of pancreatic ductal adenocarcinoma and prevents the emergence of resistance. This triple combination is well tolerated in mice,” the authors write.

A Long Road to the Clinic

Despite the remarkable preclinical results, Barbacid has been characteristically cautious about expectations. The therapy that eliminated tumors in mice must still prove itself safe and effective in humans, a journey fraught with potential obstacles.

“It is important to understand that, although experimental results like those described here have never been obtained before, we are not yet in a position to carry out clinical trials with the triple therapy,” Barbacid emphasizes. The path forward requires substantial funding, regulatory approvals for combining the three drugs, and careful assessment of how the treatment behaves in human patients.

The researchers acknowledge the challenges explicitly in their paper, noting that optimizing the triple combination for clinical use will not be easy. Nevertheless, they express hope that clinical trials could begin within approximately three years if progress continues at an appropriate pace.

The Urgency of Progress

The statistics underlying pancreatic cancer research convey both the gravity of the disease and the necessity of new approaches. In 2025, an estimated 67,440 Americans will be diagnosed with pancreatic cancer, and approximately 51,980 will die from it. The disease is projected to become the second leading cause of cancer-related deaths in the coming years, surpassing colorectal cancer.

Only about 15 percent of patients are diagnosed early enough for surgical removal of their tumors, the only currently curative option. For those with localized disease caught early, five-year survival has improved to roughly 44 percent. But for the majority diagnosed with advanced disease, prognosis remains grim, with survival typically measured in months rather than years.

The modest improvements in survival statistics over the past decade have come primarily from better management of early-stage patients and increased use of treatments before and after surgery. For metastatic disease, survival has barely budged. This context explains why even incremental advances in targeting KRAS are celebrated, and why the Spanish team’s achievement of complete, resistance-free tumor elimination in animal models has generated substantial excitement.

Looking Forward

A companion study from the same research group has provided additional insights into how KRAS-blocking drugs work throughout the body. By completely eliminating KRAS expression in healthy adult mice, the researchers found that while the gene is not essential for overall survival, its absence does affect blood cell formation and the immune system. These findings may help predict and manage potential side effects as KRAS inhibitors move toward broader clinical use. “Everything indicates that more selective molecules and drug combinations will emerge in the future, leading to more personalized medicine,” Zamorano notes.

The broader landscape of KRAS drug development has accelerated dramatically in recent years. More than 60 drugs targeting various aspects of KRAS signaling are now in development, including compounds designed specifically for the G12D mutation common in pancreatic cancer. The success of the Spanish team’s triple combination suggests that future treatments may need to attack the cancer’s molecular machinery at multiple points simultaneously, transforming what was once considered an undruggable target into a vulnerable one.

For the millions worldwide who will face a pancreatic cancer diagnosis in coming years, the work represents something that has been in desperately short supply: genuine hope. The road from mouse models to effective human treatments remains long and uncertain, but for the first time in forty years of KRAS research, scientists have demonstrated that complete elimination of these aggressive tumors is possible. The beam has been fixed at three points, and it is holding.

Sources

1. Liaki V, Barrambana S, Guerra C, Barbacid M, et al. A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance. Proceedings of the National Academy of Sciences (PNAS), 2025.

2. Zamorano-Dominguez E, et al. Systemic KRAS ablation disrupts myeloid cell homeostasis in adult mice. Proceedings of the National Academy of Sciences (PNAS), 2025.

3. Spanish National Cancer Research Centre (CNIO). Press release: The group led by Barbacid at CNIO completely eliminates pancreatic tumours in mice with no resistance developing. January 2026.

4. American Cancer Society. Cancer Statistics 2025. Atlanta: American Cancer Society, 2025.

5. Pancreatic Cancer Action Network. Five-Year Survival Rate for Pancreatic Cancer Stalls at 13%. Press Release, January 2025.

6. Drug Target Review. Drug trio found to block tumour resistance in pancreatic cancer. January 2026.

7. National Cancer Institute SEER Program. Cancer Stat Facts: Pancreatic Cancer.

8. Luo J. KRAS mutation in Pancreatic Cancer. PMC, National Institutes of Health.

9. Lustgarten Foundation. From Undruggable to Unstoppable: The State of KRAS Drug Development in Pancreatic Cancer. October 2025.