Pancreatic cancer is one of medicine's most feared diagnoses. Unlike many cancers where early detection enables cure, pancreatic ductal adenocarcinoma (PDAC) — accounting for around 90% of pancreatic cancer cases — is typically detected late, spreads quickly, and defeats almost every treatment tried against it.
The five-year survival rate remains below 12%. It kills around **466,000 people globally each year**.
The reason it's so hard to treat comes down to a single, frustrating problem: **drug resistance**. Pancreatic tumours have evolved into resistance machines. Target one pathway, and alternative pathways activate to keep the tumour growing. This is why single-drug and even two-drug treatments so frequently fail over time.
Now, a team at Spain's **National Cancer Research Centre (CNIO)**, led by Professor Mariano Barbacid — one of the world's leading pancreatic cancer researchers — has published results in **PNAS** (Proceedings of the National Academy of Sciences) that represent a significant leap forward.
**The Three-Drug Strategy**
Rather than attacking one pathway, the CNIO team simultaneously targeted **three critical signalling pathways** that pancreatic cancer relies on to survive and to develop resistance.
The three drugs:
1. **Daraxonrasib** — an experimental KRAS inhibitor. The KRAS gene is mutated in roughly 90% of pancreatic cancers, making it the central driver. KRAS inhibitors have only recently become clinically available.
2. **Afatinib** — an FDA-approved drug originally for lung cancer, which inhibits EGFR and HER2 kinase signalling — pathways that tumours frequently activate when KRAS is blocked.
3. **SD36** — a newer compound targeting STAT3, another signalling molecule that tumours use as an escape route from KRAS inhibition.
The logic is elegant: when you block KRAS, tumours escape via EGFR/HER2. Block those too, and they escape via STAT3. Block all three simultaneously, and there's nowhere to run.
**The Results**
In multiple preclinical models — including genetically engineered mice that develop pancreatic cancer, and human tumour samples grown in mice — the triple combination achieved:
- ✅ **Complete tumour regression** — tumours disappeared entirely - ✅ **Durable response** — no tumour return for at least **200 days** after treatment - ✅ **Drug resistance blocked** — the mechanisms that allow tumours to escape were simultaneously shut down - ✅ **Good tolerability** — no significant toxicity, weight loss, or organ damage in treated mice
The complete and sustained regression across multiple model types is what distinguishes this from many earlier promising studies.
**What This Means — And What It Doesn't**
Honesty matters here. These are **preclinical results** — in mice and human cell models, not yet in human trials. The history of cancer research includes many compounds that worked brilliantly in animals and then failed in humans.
Clinical trials for this specific triple combination in human patients have not yet begun.
However, several factors make researchers cautiously optimistic about eventual translation:
- Two of the three drugs are already in human use or human trials, meaning their safety profiles are partially known - The mechanistic logic — simultaneously blocking three resistance pathways — is grounded in well-established cancer biology - The preclinical results are unusually strong and consistent across multiple model types
**The Broader Moment**
This study arrives at a genuinely exciting time in pancreatic cancer research. KRAS inhibitors — once considered "undruggable" — have finally entered the clinic. Combination therapies are replacing single-drug approaches. The CNIO results, alongside other combination approaches being explored globally, suggest that pancreatic cancer's near-impenetrable resistance may finally have a systematic solution.
Professor Barbacid has spent decades working on KRAS-targeted pancreatic cancer. He describes these results as representing "a new therapeutic strategy that could be the key to improving survival rates for patients with this devastating disease."
Four hundred and sixty-six thousand people die of pancreatic cancer every year. Every meaningful step forward is a step worth taking. 🔬💙
*Sources: PNAS (March 2026) · CNIO (Spanish National Cancer Research Centre) · SciTechDaily · LiveScience · Drug Target Review · Mariano Barbacid Lab*
