THE pancreatic cancerThis disease, which is very difficult to detect and treat, is one of the deadliest, with a five-year survival rate of barely 5%. And unfortunately, the number of cases continues to rise, probably due to environmental factors, such as exposure to pesticides and the alcohol consumptionBut a glimmer of hope shines on the horizon: researchers from the Spanish National Cancer Research Center (Centro Nacional de Investigaciones Oncologicas) presented in December 2025 in PNASA triple therapy that successfully eliminates the tumor in mice. Interview with Carmen Guerra, one of the study's directors.
Science and the Future: Why is pancreatic cancer so deadly?
Carmen Guerra: Partly because it's diagnosed very late. Patients who are lucky enough to be diagnosed very early can have surgery and be cured, or have a much longer life expectancy. But generally, when patients consult a doctor about symptoms related to this cancer, it's already too late, and there are often metastases. And once you have metastases, surgery is difficult.
Why is this cancer so difficult to detect?
At first, the tumor shows no signs, it doesn't cause pain, until it invades a nerve, and then it's usually too late. When the patient experiences pain or digestive problems, it's already too late.
"Currently, there are few specific treatments for these tumors."
What is the usual treatment?
After diagnosis, patients who are not candidates for surgery are generally treated with cytotoxic drugs or chemotherapy, such as gemcitabine or FOLFIRINOX. However, these treatments damage not only the tumor cells but also the rest of the body. Furthermore, there is almost always a very rapid recurrence; the tumor reappears. Currently, there are few specific treatments for these tumors. Fortunately, specific drugs have recently been developed that inhibit KRAS, the initiating oncogene responsible for most pancreatic tumors (90 %). These inhibitors show good results and significantly increase survival compared to chemotherapy, but unfortunately, after a certain period, the tumor usually develops resistance and begins to grow again.
What is the initial function of KRAS and why is it such a potent oncogene?
KRAS is a gene expressed in all cells of the body. It is essential for cell proliferation and survival and also controls important cell signaling functions. However, when it acquires an activating mutation, which makes its activity much higher and uncontrolled, these cells proliferate significantly. And in proliferating in this way, the cells acquire many more mutations. This oncogenic activity of the KRAS gene is found primarily in lung and pancreatic cells. In these two organs, it is the initiating oncogene.
And how does this resistance to KRAS inhibitors develop?
These tumor cells are so aggressive that they seek alternative ways to overcome this inhibition (for example, by amplifying the region of the chromosome that codes for this protein, thus generating many more copies of KRAS and making its inhibition more difficult). This creates resistance to treatment; the tumor survives and begins to grow again.
How did you manage to overcome this resistance?
In a work we carried out in 2019 (published in the journal Cancer CellWe observed that inhibiting EGFR and RAF1 (two proteins in the same signaling pathway as KRAS) reduced tumor size by 50%. However, 50% of these % tumors were resistant. We therefore investigated this resistance mechanism and found it to involve the STAT3 pathway, a transcription factor (a protein that regulates gene expression). By inhibiting all three proteins simultaneously (EGFR, RAF1, and STAT3), we were fortunately able to completely inhibit tumor growth in mice.
"In two or three years, we will be able to begin clinical trials on patients."
And was this effect lasting over time?
Yes, not only did the tumor disappear, but it didn't reappear, at least for 200 days (the duration of the experiment), which is roughly a quarter of a mouse's lifespan. The pancreases were completely clear. We couldn't even see where the tumor had started. To be honest, we weren't expecting such a positive result. But we can't yet evaluate it in patients.
For what ?
For reasons of tolerability. Daraxonrasib, the KRAS inhibitor used, is very well tolerated and has very low toxicity compared to chemotherapy, but it still has side effects. In some patients, for example, skin sensitivity, colitis (inflammation of the colon), vomiting, fatigue, and other problems are observed. But the second drug, afatinib, an EGFR inhibitor, although approved for lung cancer patients, is more toxic than daraxonrasib. And if we combine them, we should expect the side effects to be even more significant, perhaps even intolerable for patients. As for the third inhibitor, which is currently a STAT3 degrader, although it has not shown toxicity in mice, we don't know what will happen in patients.
So what is the next step in finding a safe treatment for humans?
We are trying to improve the pharmacology, to find alternatives to afatinib and the STAT3 degrader we use. For the latter, we are collaborating with a small biotechnology company (Vega Oncotargets). And we are on the right track; we have already been working on improving this drug for a year. I think that in about two years, we will have developed drugs that, when combined, will be less toxic than those we currently have. In two or three years, we will be able to begin clinical trials on patients. That is our goal. In parallel, we are studying the use of this triple therapy in metastases, to see if it could also be effective when the cancer has already metastasized.
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