Spanish Researchers Achieve Complete Regression of Pancreatic Tumours in Mice Using Triple Therapy

A team led by Mariano Barbacid at Spain’s National Cancer Research Centre (CNIO) has developed an experimental triple-drug combination that completely eliminated pancreatic tumours in mouse models, with no tumour recurrence observed and minimal side effects reported.

The breakthrough addresses one of the major challenges in treating pancreatic ductal adenocarcinoma (PDAC), the most common and aggressive form of pancreatic cancer, which is driven primarily by mutations in the KRAS gene. Single-agent KRAS inhibitors have shown initial promise but often fail as tumours develop resistance within months. According to details received by The Chenab Times, the new approach combines three targeted agents to simultaneously block multiple survival pathways in cancer cells, preventing resistance and leading to durable tumour elimination in preclinical tests.

The study, published in the Proceedings of the National Academy of Sciences (PNAS), was co-led by Carmen Guerra, with Vasiliki Liaki and Sara Barrambana as first authors. It tested the therapy—comprising daraxonrasib (a KRAS inhibitor), afatinib (an approved irreversible EGFR/HER2 inhibitor used in lung cancer), and SD36 (a selective STAT3 protein degrader)—across three different mouse models. These included genetically engineered mice predisposed to develop PDAC, mice implanted with human pancreatic tumour tissue, and those with surgically implanted cancer cells.

In all models, the triple therapy induced complete tumour regression. In one set of experiments, treated mice showed no signs of tumour regrowth for at least 250 days. In another involving human tumour implants, 16 out of 18 animals achieved full regression, with observations limited to 80 days due to the immunocompromised nature of the host mice. The treatment was well tolerated, with no significant toxicity reported across the animals.

Barbacid, head of the Experimental Oncology Group at CNIO and a pioneer in oncogene research since isolating the first human oncogene in the 1980s, emphasised the importance of multi-pathway targeting. Previous efforts focusing solely on KRAS inhibition have been limited by adaptive resistance mechanisms, including activation of alternative signalling routes such as EGFR/HER2 and stress-response pathways involving STAT3. By hitting these concurrently, the combination disrupts tumour survival more comprehensively.

Pancreatic cancer remains one of the deadliest malignancies worldwide, with a five-year survival rate often below 10 per cent in many regions due to late diagnosis and limited effective therapies. The disease claims hundreds of thousands of lives annually, underscoring the urgency for new approaches. This preclinical success has generated significant interest, as it represents an unprecedented level of tumour elimination without resistance in animal models of PDAC.

However, the researchers cautioned that substantial hurdles remain before human application. Clinical trials cannot yet proceed with this specific triple combination, as further optimisation, safety profiling, and regulatory steps are required. Barbacid noted that while these results are highly encouraging and pave the way for designing improved combined therapies, they are still at the experimental stage.

The findings build on decades of work by Barbacid’s group and others in understanding KRAS-driven cancers. They highlight the potential of combination targeted therapies over monotherapy in overcoming resistance, a common barrier in oncology. International experts have described the work as a promising step toward better outcomes for patients, though years of additional research lie ahead to translate these mouse model results into viable human treatments.