The Molecular Oncology Group at Spain’s National Center for Cancer Research (CNIO) has developed a new triple combination therapy that completely eliminates pancreatic tumors in mouse models without triggering drug resistance. This breakthrough addresses a critical issue where current pancreatic cancer drugs lose effectiveness within months due to tumor adaptation.
Pancreatic cancer remains one of the deadliest cancers, with over 10,300 new cases annually in Spain alone and a five-year survival rate under 10%. The disease is typically diagnosed at advanced stages, limiting therapeutic options and efficacy. The CNIO team’s findings, published in the journal PNAS (Proceedings of the National Academy of Sciences), provide a promising route to enhance patient outcomes through strategic molecular intervention.
Targeting KRAS from Multiple Angles
The researchers focused on KRAS, a gene mutated in approximately 90% of pancreatic ductal adenocarcinomas, which drives tumor growth. Although KRAS inhibitors recently approved for experimental use marked a significant innovation after decades of limited progress, their benefits have been short-lived due to rapid tumor resistance.
Mariano Barbacid, head of CNIO’s Experimental Oncology Group, explained that their novel approach inhibits KRAS signaling at three distinct points, rather than a single target. "Blocking the oncogene KRAS at three sites reduces the likelihood of tumor escape mechanisms," the study details. Genetically disabling these three molecules in mice resulted in permanent tumor regression without evident side effects.
Triple Therapy Composition
The team translated this strategy pharmacologically by combining:
- Daraxorasib – an experimental KRAS inhibitor.
- Afatinib – an approved drug for certain lung adenocarcinomas.
- SD36 – a protein degrader facilitating targeted molecule degradation.
This triple regimen was tested in three different mouse models of pancreatic ductal adenocarcinoma. In all cases, treatment yielded significant and durable tumor regression with no major toxicities reported, indicating both efficacy and tolerability.
Preclinical Success and Future Directions
The study authors highlight, “This combined triple therapy induces robust regression of pancreatic adenocarcinoma models and prevents the development of resistance.” However, Barbacid cautions that despite unprecedented preclinical outcomes, the therapy is not yet ready for human clinical trials. Clinical translation will require further optimization and safety evaluations.
They emphasize the complexity involved in adapting this triple inhibition for patients but remain optimistic it could lead to new therapeutic options for pancreatic cancer survivors in the near future.
Funding and Institutional Context
This research received support from multiple sources including the CRIS Foundation Against Cancer, the European Research Council (ERC), Spanish governmental bodies, and EU Next Generation funds. CNIO is Spain’s largest cancer research center and a leading institution in Europe, dedicated to advancing cancer prevention, diagnosis, and treatment through multidisciplinary science.
The progress demonstrated by the CNIO group may mark a pivotal turning point in pancreatic cancer therapy by addressing drug resistance at a molecular signaling network level. This innovative strategy paves the way for designing future clinical trials aimed at extending survival and improving quality of life for pancreatic cancer patients worldwide.
Read more at: www.cnio.es