Healthcare
Triple-Targeted Drug Combination Shows Promise Against Pancreatic Cancer
Pancreatic cancer is one of the most aggressive and lethal malignancies, with survival rates that have barely improved over decades. Now, a new preclinical study suggests that a triple-targeted drug combination could offer a powerful way to overcome tumour resistance, one of the biggest barriers to effective treatment.
Researchers at the Spanish National Cancer Research Centre report that simultaneous targeting of three critical signalling pathways in pancreatic ductal adenocarcinoma (PDAC) led to complete and durable tumour regression across multiple preclinical models. The findings highlight a potential new direction for tackling a cancer that is often resistant to standard therapies.
Why Pancreatic Cancer Is So Hard to Treat
PDAC, the most common form of pancreatic cancer, is driven in most cases by mutations in the KRAS gene, often alongside TP53 alterations. These mutations activate multiple survival and growth pathways, allowing tumours to adapt and develop resistance when only a single pathway is blocked.
Traditional targeted therapies have struggled to produce long-lasting results in PDAC, largely because cancer cells rapidly rewire their signalling networks. This new study aimed to shut down those escape routes by attacking several critical nodes at once.
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The Triple Inhibition Strategy Explained
The researchers designed a combination therapy that targets three interconnected signalling pathways essential for tumour survival:
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RMC-6236 (daraxonrasib): A KRAS-targeting agent
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Afatinib: An inhibitor of EGFR family receptors
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SD36: A selective degrader of STAT3 signalling
By blocking KRAS-related signalling downstream, upstream and in parallel survival pathways, the therapy effectively cut off the tumour’s ability to adapt.
In orthotopic mouse models—where tumours grow in the pancreas rather than under the skin—the combination not only shrank tumours but completely halted their growth. Remarkably, no tumour resistance was observed for more than 200 days after treatment.
Big breakthrough in pancreatic cancer research 🧬
A team led by Spanish oncologist Mariano Barbacid wiped out KRAS-mutant pancreatic tumors in mice using a low-toxicity 3-drug combo:
Gemcitabine + ATRA + Neratinib.Published in PNAS (Jan 27, 2026).
— DOCTORS SQUAD 🩺 (@doctors_squad) January 29, 2026
Broad Efficacy Across Preclinical Models
The anti-tumour effects were not limited to a single model. The drug trio also drove significant regression in genetically engineered mouse tumours and in patient-derived tumour xenografts, which use human pancreatic cancer tissue grown in mice.
Equally important, the treatment was well tolerated in animals, suggesting a potentially favourable safety profile for future clinical testing. This balance of efficacy and tolerability is critical when considering translation into human trials.
Implications for Future Cancer Therapies
Resistance remains one of the biggest challenges in oncology, particularly in pancreatic cancer. By targeting multiple signalling nodes simultaneously, this triple-drug approach appears to prevent tumours from finding alternative survival pathways—at least in preclinical settings.
While human trials are still needed, these findings provide strong justification for developing new clinical studies based on multi-targeted combination therapies. If replicated in patients, this strategy could mark a significant step forward in the treatment of one of the deadliest cancers.
