Permanent Disappearance of Pancreatic Cancer Achieved in New Triple-Drug Mouse Study

Pancreatic cancer remains one of medicine’s most stubborn enemies. It kills fast, hides well, and resists almost every drug we throw at it. But a team of researchers in Spain may have found a way to beat it at its own game. Scientists at the Spanish National Cancer Research Centre (CNIO) developed a triple-drug therapy that eliminated pancreatic tumors in mice and kept the cancer from returning. Even more promising: the treatment caused no toxic side effects. While human trials are still ahead, these results open a door that many oncologists feared would stay shut for decades.

Why Pancreatic Cancer Kills So Fast

Pancreatic cancer carries one of the lowest survival rates among all common cancers. Only about 13% of patients survive five years past diagnosis. For people caught at a late stage, that number drops to just 1%.

Part of what makes pancreatic cancer so lethal is its silence. Early tumors grow deep inside the abdomen without causing clear symptoms. By the time doctors detect them, cancer has often spread to the liver, lungs, or other nearby organs. At that point, surgery is no longer an option for most patients.

Common symptoms like jaundice, unexplained weight loss, fatigue, appetite changes, and digestive problems tend to appear late. In the UK alone, more than half of pancreatic cancer patients die within three months of diagnosis, and about 80% receive their diagnosis after the cancer has already spread.

Your pancreas produces hormones like insulin and glucagon, which help convert food into energy. Cancer in the gland disrupts hormone production and can cause unstable blood sugar, adding another layer of danger to an already aggressive disease.

KRAS: A Mutant Gene That Drives 90% of Cases

Nearly all pancreatic cancers share a common villain: a mutated version of a gene called KRAS. In healthy cells, KRAS acts like a switch that controls cell growth and division. It turns on when cells need to multiply and turns off when they don’t.

But when KRAS mutates, it gets stuck in the “on” position. Cells begin dividing without any brakes, and cancer takes root. About 90% of pancreatic ductal adenocarcinoma (PDAC) cases carry a KRAS mutation, making it the most common starting event for the disease.

For decades, scientists considered KRAS “undruggable.” No one could find a way to block it with medicine. A breakthrough came when researchers discovered a small pocket in the KRAS protein where drugs could latch on. Drug developers created compounds like sotorasib and adagrasib, which gained FDA approval for certain KRAS mutations. More recent drugs, called RAS(ON) inhibitors, can block multiple KRAS mutations at once. One of them, daraxonrasib (also known as RMC-6236), has already shown promise in clinical trials for PDAC patients.

How Cancer Outsmarts Single Drugs

Even with new KRAS inhibitors, pancreatic cancer finds ways to survive. When a drug blocks one growth pathway, tumors adapt and activate backup routes to keep multiplying. Doctors call this tumor resistance, and it remains one of the biggest obstacles in cancer treatment.

Standard chemotherapies like gemcitabine attack all fast-dividing cells in the body. While they can slow tumor growth, they cause heavy collateral damage to healthy tissue. And despite the side effects, tumors still develop resistance over time.

Carmen Guerra, a cancer biologist at CNIO and senior author of the new study, had seen this pattern before. Her earlier work showed that blocking two KRAS-related pathways (RAF1 and EGFR) could shrink small tumors. But larger tumors adapted and continued to grow. When her team analyzed those resistant tumors, they found a protein called STAT3 had become active. STAT3 served as an emergency backup, keeping cancer cells alive even when other growth pathways were shut down.

Blocking Three Escape Routes at Once

Armed with that discovery, Guerra and her colleagues designed a strategy to block all three pathways at the same time. Led by Dr. Mariano Barbacid, a prominent figure in cancer research, the team first confirmed the concept through genetic experiments. When they shut down KRAS signaling, EGFR, and STAT3 in mouse tumor cells, the cancer died. Removing any two of the three was not enough. As long as tumor cells kept even one pathway active, they survived.

Next, the team built a drug-based version of the strategy using three compounds: daraxonrasib (a RAS inhibitor already in clinical trials), afatinib (an EGFR/HER2 inhibitor approved for certain lung cancers), and SD36 (a newer compound designed to destroy the STAT3 protein).

All three drugs need to work together. When the team tested two-drug combinations, tumors shrank but did not disappear. Only the full triple therapy produced complete tumor elimination. And there was a critical timing element: all three drugs had to be given at the same time. Cancer cells that first became resistant to daraxonrasib alone did not respond when afatinib and SD36 were added later.

What Happened in Mouse Models

Researchers tested their triple therapy in three different mouse models to cover a range of scenarios. One model used mouse tumor cells implanted into the pancreas. A second used mice genetically engineered to develop pancreatic cancer on their own. A third grew human tumor samples in mice with suppressed immune systems. In all three models, the triple-drug combination eliminated tumors completely.

Guerra described the results in striking terms: the pancreas looked completely healthy after treatment. You could not even see where the tumor had been.

Even more striking, tumors did not return for at least 200 days (about seven months) after treatment ended. Most single-drug therapies in similar mouse models fail much sooner. When researchers examined pancreatic tissue at the end of the experiment, they found no trace of tumor or surrounding scar tissue.

Human tumor samples grown in mice also responded well. When the team swapped daraxonrasib for a different KRAS inhibitor called MRTX-1133, the therapy still worked, suggesting the approach is flexible across different drug options.

No Toxic Side Effects in Mice

One of the most encouraging parts of the study: the triple therapy appeared safe for the animals. Mice receiving the treatment maintained healthy body weight, normal blood counts, stable metabolic markers, and intact organ tissue compared to untreated mice.

Earlier attempts to target similar pathways had produced dangerous results. When the team tried replacing SD36 with dasatinib (a drug that blocks the SRC family of proteins, which activate STAT3), the combination caused fatal gastrointestinal bleeding in mice within 24 hours. Several related drugs produced the same toxic outcome, confirming that not just any STAT3-blocking strategy will work safely.

From Mice to Humans: A Long but Hopeful Road

While the results are exciting, important caveats remain. All the data so far come from mice, not human patients. Guerra noted that mice can tolerate certain drug toxicities better than humans. Afatinib, for example, already causes known side effects in people, including skin and gastrointestinal problems. And the dose used in mice (20 mg/kg) far exceeds what current clinical trials use for PDAC patients (about 0.6 mg/kg).

Laboratory mice in these studies were also young and otherwise healthy, unlike many human pancreatic cancer patients who are older and may have other medical conditions.

Pancreatic tumors are also genetically diverse. Each patient carries different mutations, which means a single treatment approach may not work for everyone. Guerra’s team plans to test additional KRAS mutations and other cancer-related gene changes in future mouse models.

Researchers are now working to find better-tolerated versions of the drugs, especially for the EGFR and STAT3 targets. EGFR degraders (drugs that destroy the protein rather than just blocking it) and newer oral STAT3 compounds may offer safer alternatives for human use.

Why Combination Therapy May Be the Path Forward

Perhaps the most important takeaway from the study is a simple but powerful concept: pancreatic cancer cannot be beaten with a single drug. When researchers blocked one or two pathways, tumors found workarounds. Only when all three escape routes were shut down at once did the cancer have nowhere to go.

As the study authors wrote in PNAS, their results should guide new clinical trials that may benefit PDAC patients. Spain’s government took notice too, with the Embassy of Spain in the UK sharing the achievement publicly.

For a cancer that has resisted treatment for decades, a triple-drug approach that produces complete, lasting tumor elimination in mice, without toxic side effects, represents a rare and meaningful step forward. Human trials will tell us whether that promise can become reality.

My Personal RX on Protecting Your Pancreatic Health

Pancreatic cancer often goes undetected until late stages, which makes prevention and early awareness even more important. While we cannot control every risk factor, we can take daily steps to support our pancreatic health and lower our cancer risk. A well-nourished gut, a clean diet, quality sleep, and regular movement all contribute to a body that can better resist disease. I always tell my patients: your daily habits are your first line of defense. You do not need to wait for a diagnosis to start protecting yourself. Here are my recommendations:

1. Load Your Plate with Colorful Plants: Fruits, vegetables, whole grains, legumes, and nuts feed beneficial gut bacteria and promote healthy digestion. Aim for at least five servings of produce per day to keep your pancreas and entire digestive system working well.
   
2. Limit Red and Processed Meats: High intake of processed meats and red meat has been linked to increased pancreatic cancer risk. Replace them with fish, poultry, or plant-based proteins several times per week.
   
3. Prioritize Restorative Sleep: Poor sleep raises inflammation and weakens your immune defenses. Sleep Max contains magnesium, GABA, 5-HTP, and taurine to calm your mind, balance neurotransmitters, and promote deep REM sleep so your body can repair itself each night.
   
4. Know Which Supplements Your Body Needs: After age 40, your body absorbs fewer key nutrients. Download my free guide, The 7 Supplements You Can’t Live Without, to learn which supplements fill the gaps, which “healthy” foods may be fooling you, and how to spot quality supplements in seconds.
   
5. Move Your Body Every Day: Regular physical activity improves digestion, reduces inflammation, and supports healthy blood sugar levels. Even a 30-minute walk can make a measurable difference for your pancreatic health.
   
6. Cut Back on Sugar and Alcohol: Excess sugar strains your pancreas by forcing it to overproduce insulin. Alcohol adds to that burden. Reducing both protects your pancreas from chronic stress and lowers your cancer risk.
   
7. Talk to Your Doctor About Screening: If you have a family history of pancreatic cancer or carry known risk factors like chronic pancreatitis or diabetes, discuss early screening options with your healthcare provider. Early detection saves lives.
   
8. Pay Attention to Digestive Warning Signs: Do not ignore persistent bloating, unexplained weight loss, new-onset diabetes, or changes in stool color. Bring these symptoms to your doctor promptly for evaluation.
   

Source: Liaki, V., Barrambana, S., Kostopoulou, M., Lechuga, C. G., Zamorano-Dominguez, E., Acosta, D., Morales-Cacho, L., Álvarez, R., Sun, P., Rosas-Perez, B., Barrero, R., Jiménez-Parrado, S., López-García, A., Roman, M. S., López-Gil, J. C., Drosten, M., Sainz, B., Musteanu, M., Caleiras, E., . . . Barbacid, M. (2025). A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance. Proceedings of the National Academy of Sciences, 122(49), e2523039122. https://doi.org/10.1073/pnas.2523039122