Pancreatic cancer is one of the most aggressive and deadly forms of cancer. One major reason for its poor survival rate is that current treatments often stop working within months.
Even newer targeted drugs that were designed to attack the cancer more precisely tend to lose their effectiveness quickly because the tumor adapts and becomes resistant. Now, researchers in Spain report a major breakthrough that could change how this disease is treated in the future.
A research team at Spain’s National Cancer Research Centre has developed a new triple-drug treatment that completely eliminated pancreatic tumors in mice and prevented the cancer from coming back.
Even more importantly, the tumors did not develop resistance to the therapy, and the treatment caused no major side effects in the animals. The findings were published in the journal Proceedings of the National Academy of Sciences.
The work was led by Mariano Barbacid, head of the Experimental Oncology Group at the CNIO and a long-time leader in pancreatic cancer research. The study was co-led by Carmen Guerra, with Vasiliki Liaki and Sara Barrambana as first authors. Together, the team tackled one of the biggest challenges in pancreatic cancer treatment: drug resistance.
Most pancreatic cancers belong to a type called pancreatic ductal adenocarcinoma. This cancer is extremely difficult to treat because it is usually detected late and responds poorly to therapy. For decades, treatment options barely improved beyond standard chemotherapy. It was not until 2021 that the first drugs targeting specific cancer-driving genes were approved.
These newer drugs focus on KRAS, a gene that is mutated in about 90 percent of pancreatic cancer cases. The KRAS mutation acts like a stuck accelerator pedal, forcing cancer cells to grow and divide uncontrollably.
Blocking KRAS was long considered impossible, so the approval of KRAS inhibitors was seen as a major step forward. However, the benefits have been limited. In most patients, the tumor adapts within a few months and becomes resistant, allowing the cancer to grow again.
The CNIO team approached this problem from a different angle. Instead of blocking KRAS at just one point, they decided to shut down the cancer-driving pathway at three separate points.
The idea is similar to securing a heavy object with multiple supports rather than just one. If one support fails, the others still hold it in place. By targeting multiple links in the same chain, it becomes much harder for the tumor to escape.
In earlier experiments, the researchers genetically removed three key molecules involved in the KRAS signaling pathway in mouse models of pancreatic cancer. When they did this, the tumors disappeared completely and did not return. This result suggested that a similar approach using drugs might be possible.
To test this idea, the team designed a triple-drug therapy. The combination included an experimental KRAS inhibitor called daraxonrasib, an already approved cancer drug called afatinib, which is used in some lung cancers, and a protein degrader known as SD36.
Each drug blocks the KRAS pathway in a different way, creating a strong and coordinated attack on the cancer cells.
The researchers tested this triple therapy in three different mouse models of pancreatic ductal adenocarcinoma. In all cases, the tumors shrank dramatically and then disappeared. Most importantly, the cancer did not return even after treatment ended. The mice tolerated the therapy well, with no serious toxic effects observed.
This is a striking result because resistance has been one of the biggest barriers to effective pancreatic cancer treatment. According to the researchers, this is the first time such strong and lasting tumor regression has been achieved in experimental models using drug combinations that target the KRAS pathway.
Despite the excitement, the scientists stress that this does not mean the treatment is ready for patients yet. Moving from animal studies to human clinical trials is a long and complex process. The doses, timing, and safety of the drug combination would need to be carefully optimized before testing in people.
Mariano Barbacid emphasized that while the results are unprecedented, more work is needed. Translating this triple therapy into a form suitable for clinical use will not be easy. However, he and his colleagues believe the findings open the door to new ways of thinking about pancreatic cancer treatment.
In reviewing the study, its strengths are clear. The therapy was tested in multiple animal models, produced complete tumor elimination, prevented resistance, and showed good safety.
At the same time, the study is limited to mice, and animal success does not always translate directly to human patients. Still, the results represent a major step forward in understanding how resistance might be avoided.
Overall, this research offers new hope for a cancer that has long resisted medical progress. By attacking pancreatic cancer at multiple weak points at once, scientists may eventually be able to turn a once untreatable disease into one that can be controlled more effectively.
While clinical use is still some distance away, this study sets a clear direction for future trials and brings renewed optimism to a field in urgent need of better options.
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