A new study reports that a triple-targeted drug combination can drive complete and lasting regression of pancreatic tumours in preclinical models, potentially overcoming treatment resistance in one of the deadliest cancers.
Researchers at the Spanish National Cancer Research Centre have announced a potential breakthrough combination therapy that induces complete regression of pancreatic tumours and prevents tumour resistance in preclinical models.
The study describes a targeted combination therapy that simultaneously targets three key signalling pathways in pancreatic ductal adenocarcinoma (PDAC), the most common and lethal type of pancreatic cancer.
Triple inhibition strategy
Pancreatic cancer remains notoriously difficult to treat, with very poor survival rates and limited effective therapies. The new research aims to combat this by targeting RAF1, EGFR family receptors and STAT3 signalling – nodes that are crucial for tumour growth and survival.
According to the authors, “genetic ablation of three independent nodes involved in downstream (RAF1), upstream (EGFR) and orthogonal (STAT3) KRAS signalling pathways leads to complete and permanent regression of orthotopic PDACs induced by KRAS/TP53 mutations.”
The triple treatment combines three drugs:
- RMC-6236 (daraxonrasib): targeting KRAS
- Afatinib: an EGFR family inhibitor
- SD36: a selective STAT3 degrader
These agents together were tested in orthotopic mouse models of PDAC, where tumour cells are implanted in a location that closely resembles their natural environment in the pancreas. The results demonstrated the therapy not only reduced tumour size but also entirely stopped tumour growth with no evidence of tumour resistance for more than 200 days after treatment.
Broad efficacy in preclinical models
Researchers extended their observations beyond engineered mouse models. The combination therapy also led to significant regression in genetically engineered mouse tumours and in human cancer tissues grown in lab mice, known as patient-derived tumour xenografts (PDX).
These results should guide the development of new clinical trials that may benefit PDAC patients.
These powerful anti-tumour effects were achieved with a therapy that was well tolerated in the animals, which could provide a favourable safety profile for future clinical testing.
“These results should guide the development of new clinical trials that may benefit PDAC patients,” said the authors.
A step towards overcoming resistance
One of the most significant hurdles in targeted cancer therapies is the development of resistance. This new combination strategy appears to prevent this relapse, at least in preclinical models, by attacking multiple nodes of tumour signalling simultaneously.
According to commentary from scientists involved in the work: “Overcoming therapeutic resistance in PDAC requires coordinated inhibition of KRAS downstream (RAF1), upstream (EGFR) and parallel survival pathways (STAT3).”
Clinical implications
While more research will be needed before trials in humans can begin, these findings are an important advancement in the search for better pancreatic cancer therapies. By demonstrating complete and durable tumour regression without resistance in preclinical models, there is now strong potential for clinical development of multi-targeted approaches in the future.