A triple-combination treatment for pancreatic cancer has shown promise in early animal tests, pointing to a potential new treatment for a disease with a notoriously poor survival rate.
Considered one of the deadliest common cancerPancreatic cancer has a five-year relative survival rate of around 13% – meaning that roughly 87% of people with cancer are expected to die within five years of diagnosis. This survival rate can drop by as much as 1% in people diagnosed in the very late stages of the disease.
“These studies pave the way for designing new combination therapies that can improve survival for patients with pancreatic ductal adenocarcinoma. [the most common pancreatic cancer]” said the authors of the study and declaration. “These results point the way for the development of new clinical trials.”
Early stage pancreatic cancer grows silently in the abdomen without any obvious symptoms. By the time the disease is detected, it has often already spread to other organs, making it difficult to remove surgically.
Standard treatments such as chemotherapy attack all rapidly dividing cells in the body, often causing a lot of collateral damage in the process of controlling tumor growth. And even then, tumors usually find alternative ways to multiply and become resistant to treatment.
The new therapy not only prevented the rodents’ cancer from returning, but was also generally non-toxic to the mice and showed no debilitating side effects.
Almost all pancreatic cancers are associated with a mutation in a gene called “KRAS”, which normally controls cell division and growth and keeps them in check. But when the gene is mutated, it gets stuck in the “on” position, leading to an abnormal rate of cell division and cancer.
Prior to the current research, the lead author of the study Carmen Guerraan oncology biologist from the Experimental Oncology Group of the Spanish National Center for Cancer Research (CNIO), developed mouse models to investigate how KRAS mutations and other related pathways help pancreatic tumors survive. While blocking certain KRAS-related pathways can stop small tumors from growing, larger tumors often adapt to “open another door” for survival, she told Live Science.
In their latest work, Guerra and her team analyzed these resistant tumors and found that a protein called STAT3 became highly active when other growth pathways were blocked. This suggests that it could function as an emergency backup pathway for tumor growth.
The team tried to genetically block this pathway in mouse tumor cells, along with other major tumor growth factors. And they observed that the tumors regressed, confirming that STAT3 was indeed a key “resistance mechanism,” Guerra said.
At that point, researchers confirmed that genetically turning off three pathways—KRAS, a KRAS-related pathway, and STAT3—could eliminate tumors. So they set out to test a drug-based version of the strategy.
This triple approach includes two existing drugs: afatinib, which is approved by the Food and Drug Administration for certain types of lung cancer, and daraxonrasib, which is currently being tested in clinical trials. The third drug is a newer compound designed to deactivate STAT3.
The team evaluated this three-drug therapy in three types of mouse models: one in which tumor cells from mice are implanted directly into the mouse pancreas; one involving mice that had been genetically engineered to develop pancreatic cancer; and one using human tumor samples grown in immunodeficient mice to prevent the mouse’s immune system from attacking the foreign tissue. In all three models, the combined treatment completely eliminated tumors.
“You couldn’t even see where the tumor was,” Guerra told Live Science. “The pancreas was completely healthy.
The treatment also prevented resistance, as the team reported that tumors did not return for at least 200 days — or nearly seven months — after treatment, which is longer than most single-drug therapies achieve in similar mouse models.
Importantly, the three-drug therapy did not cause toxic or severe side effects in the mice. Rodents receiving the therapy showed similar body weight, blood counts, metabolic markers and organ health compared to tumor-bearing mice placebo treatment.
However, since this new research was conducted on mice, there could be some differences in human pancreatic cancer patients. Guerra noted that mice may be “more resistant to this kind of toxicity” than humans. While the therapy showed no side effects in the mice, some of the drugs they used, such as afatinib, have already been tested in humans and are known to have some side effects, such as skin and gastrointestinal problems.
So scientists are now working to find alternatives and “develop better drugs” that target the same pathways, she told Live Science.
Guerra also emphasized that pancreatic tumors are genetically different and patients can have “tons of changes,” so each case is different from the next. On that front, the team will also study other mouse models that carry other common KRAS mutations, as well as changes in other cancer-related genes, to test the effectiveness of the therapy in different tumor types, he told Live Science.
This article is for informational purposes only and is not intended to provide medical advice.
Liaki, V., et al. (2025). Targeted combination therapy achieves effective regression of pancreatic cancer and prevents tumor resistance. Proceedings of the National Academy of Sciences, 122(49). https://doi.org/10.1073/pnas.2523039122
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