New Pancreatic Cancer Treatment Wipes Out Tumors and Blocks Drug Resistance

A triple drug approach that blocks the KRAS pathway at three points eliminated pancreatic tumors and prevented resistance in mouse models.

Existing treatments for pancreatic cancer often stop working within a few months because tumors quickly develop resistance to the drugs. Researchers at Spain’s National Cancer Research Centre (CNIO) report that they have prevented this resistance in animal studies by using a three-drug combination therapy.

The researchers say their findings “pave the way for the design of combined therapies that may improve survival,” although they caution that this progress will not immediately translate into new treatments for patients. Mariano Barbacid, head of the Experimental Oncology Group at CNIO, emphasizes that “we are not yet in a position to carry out clinical trials with this triple therapy.”

Pancreatic cancer remains one of the most aggressive cancers. In Spain alone, more than 10,300 people are diagnosed with the disease every year. Because it is usually detected at advanced stages and effective treatments remain limited, fewer than 10% of patients survive five years after diagnosis. However, scientists say research efforts are beginning to accelerate after decades of limited progress.

Barbacid, who leads the Experimental Oncology Group at the National Cancer Research Centre (CNIO), developed a treatment strategy that eliminated pancreatic tumors in mice in a durable way and without major side effects. The study appears in PNAS (Proceedings of the National Academy of Sciences). Carmen Guerra served as co-lead author, with Vasiliki Liaki and Sara Barrambana as first authors.

“These studies open the road to design novel combination therapies that may improve the survival of PDAC patients [pancreatic ductal adenocarcinoma – the most common type of pancreatic cancer],” the authors state in PNAS. “These results set the course for developing new clinical trials.”

Eliminating resistance to treatment

In 2021, drugs designed to target specific molecular drivers of pancreatic cancer were approved for the first time after more than 50 years without major improvements beyond traditional chemotherapy. These treatments focus on KRAS, a gene mutated in about 90% of pancreatic cancer cases. Although these drugs represent a significant step forward, their benefits are limited because tumors frequently adapt and become resistant within months.

Barbacid has spent decades studying KRAS and developing experimental models of pancreatic cancer, and his team focused specifically on overcoming this resistance problem.

The approach developed by the CNIO group aims to shut down the KRAS oncogene at three different points along its signaling pathway rather than targeting a single point. When only one part of the pathway is blocked, cancer cells can often bypass the blockage. By interrupting several points at once, the pathway becomes much harder for the tumor to reactivate. In mouse models, genetically removing three molecules involved in KRAS signaling caused pancreatic tumors to disappear permanently.

Targeting three links in the chain

Translating this concept into treatment requires drugs capable of blocking those same three points in the KRAS pathway. To test this strategy, the researchers combined three agents into a single therapy. The regimen included the experimental KRAS inhibitor daraxonrasib, the approved lung cancer drug afatinib, and a protein degrader known as SD36.

The team tested this three-drug combination in three separate mouse models of pancreatic ductal adenocarcinoma. In every model examined, the treatment triggered strong and long-lasting tumor regression without causing significant toxicity, according to the results reported in PNAS.

“This study describes a triple combination therapy […] that induces the robust regression of experimental PDACs and avoids the onset of tumor resistance. This triple combination is well tolerated in mice.”

Moving towards a clinical trial, but not yet

When discussing what comes next, Barbacid explains that more work is still required before the therapy can move toward testing in people. “it is important to understand that, although experimental results like those described here have never been obtained before, we are still not in a position to carry out clinical trials with the triple therapy.”

Barbacid also notes that adapting the three-drug combination for clinical use will require additional refinement and development. “(..) Despite the current limitations, these results could open the door to new therapeutic options to improve the clinical outcome of patients with pancreatic ductal adenocarcinoma in the not-too-distant future.”

Reference: “A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance” by Vasiliki Liaki, Sara Barrambana, Myrto Kostopoulou, Carmen G. Lechuga, Elena Zamorano-Dominguez, Domingo Acosta, Lucia Morales-Cacho, Ruth Álvarez, Pian Sun, Blanca Rosas-Perez, Rebeca Barrero, Silvia Jiménez-Parrado, Alejandra López-García, Marta San Roman, Juan Carlos López-Gil, Matthias Drosten, Bruno Sainz, Monica Musteanu, Eduardo Caleiras, Nelson Dusetti, Valeria Poli, Francisco Sánchez-Bueno, Carmen Guerra and Mariano Barbacid, 2 December 2025, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2523039122

This study has been funded by Fundación CRIS Contra el Cáncer; the European Research Council (ERC); the State Research Agency, through co-financing with the European Regional Development Fund; Next Generation EU funds; the Biomedical Research Networking Centre (CIBERONC); and the Carlos III Health Institute.

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