A Promising Treatment for Pancreatic Cancer

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Pancreatic ductal adenocarcinoma (PDAC), a type of pancreatic cancer, has a five-year survival rate of less than ten percent. Often diagnosed in later stages, it is one of the most lethal diseases. Pancreatic cancer is on the path to becoming the second-leading cause of cancer death by 2030, with diagnoses rising each year. Current treatments include chemotherapy, surgery, and radiation, but do not improve clinical outcomes. A recent study published in the journal Proceedings of the National Academy of Sciences of the United States of America reveals a promising treatment for PDAC.

The new study, published in August 2025, was conducted by the Experimental Oncology Group of the Centro Nacional de Investigaciones Oncológicas in Madrid and targets three proteins involved in KRAS signaling: RAF1, EGFR, and STAT3. KRAS serves as a switch for cells. When activated, it is involved in several signaling pathways that mediate cell behaviors, including proliferation, differentiation, and migration. KRAS is the most prevalent cancer-causing gene driver in human cancers. Mutations to KRAS can help tumors evade the immune system by altering gene expression in tumor cells. The three genes had previously been studied, but not in combination.

The researchers genetically engineered the mice models so that upon the addition of the drug tamoxifen to their diet, the RAF1, EGFR, and STAT3 genes were disabled. Tamoxifen-induced recombination is a common method used to study gene function. They found that loss of all three genes was needed to cause “complete regression of advanced PDACs” without any tumors developing resistance. 

Then, the researchers then used one drug to target each protein. These drugs were used together in mice under three conditions: mice engineered to develop PDAC, mice with mouse PDAC cells injected into the pancreas, and mice given human patient-derived PDAC tumors. In all cases, the tumors regressed completely and did not grow back. As with the gene experiments, no combination of two drugs was nearly as effective as all three together because the tumors would develop resistance. Additionally, the combination of drugs was considered “well tolerated” based on tissue samples from a variety of organs, and the mice retained their weight and blood count. 

There remains much work to optimize this drug combination, but it is a promising discovery for the treatment of PDAC. However, there are other important factors to consider about this potential therapy. First, drug toxicity is a concern, especially because three drugs are being used together. While the mice in the study did not appear to experience any ill effects, two of the drugs used, daraxonrasib and afatinib, are known to cause diarrhea and rashes, among other side effects. The researchers note that SD36, which targets STAT3, is not considered suitable for clinical trials because its properties are suboptimal. A new, ideally oral, inhibitor of STAT3 would need to be developed and tested.

This study provides new insight into how KRAS-related cancers, such as pancreatic cancer, can be treated without inducing drug resistance. Although there is a long way to go before beginning clinical trials, this discovery provides promising new avenues for research and hope for many impacted by cancer.

By Maggie Sullivan