Pancreatic Cancer Breakthrough 2026: Triple-Drug Therapy Completely Eradicates Tumors in Mice – New CNIO Study

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers worldwide. With a 5-year survival rate of only 13% (American Cancer Society, 2026 data) and dropping to 3% for metastatic disease, PDAC has seen little improvement in outcomes over the past decades. Late diagnosis, dense tumor stroma, and near-universal KRAS mutations (90-95% of cases) drive rapid resistance to standard chemotherapy.

A new triple drug therapy for pancreatic cancer, detailed in a December 2025/January 2026 study published in Proceedings of the National Academy of Sciences (PNAS) by researchers at Spain’s National Cancer Research Centre (CNIO), has delivered unprecedented preclinical results: complete tumor eradication in multiple rigorous mouse models with no detectable recurrence for over 200 days.

Understanding Pancreatic Cancer and the Role of KRAS MutationsPDAC originates in the pancreatic ducts and spreads aggressively. KRAS mutations lock cells into uncontrolled growth signaling. Single-agent KRAS inhibitors often fail because tumors activate compensatory pathways such as EGFR/HER2 and STAT3 signaling.

Current standard treatments (gemcitabine + nab-paclitaxel or FOLFIRINOX) offer only modest survival gains (median 11-12 months). Targeted therapies like sotorasib and adagrasib (KRAS G12C inhibitors) work in a small subset (1-2% of PDAC cases with G12C), leaving most patients without options.

This new triple drug therapy pancreatic cancer approach addresses this challenge by simultaneously blocking three critical nodes.

The Triple-Drug Combination: Mechanism of ActionThe regimen combines:

1. Daraxonrasib (RMC-6236) — A panRAS(ON) inhibitor in Phase 1/2 clinical trials that traps mutant KRAS in its active state, blocking downstream MAPK/ERK signaling.
2. Afatinib — FDA-approved irreversible inhibitor of EGFR, HER2, and HER4 receptors that prevents upstream activation of RAS pathways.
3. SD36 — A potent, selective STAT3 PROTAC (proteolysis targeting chimera) that degrades STAT3 protein, disrupting the JAK/STAT3 resistance pathway commonly upregulated after KRAS inhibition.

By targeting KRAS directly while eliminating EGFR-family bypass and STAT3-mediated survival signals, the triple combination prevents the adaptive resistance that has historically limited KRAS inhibitors in PDAC.Study Design and Key Results Across Mouse ModelsResearchers used three complementary preclinical models to ensure robustness:

• Orthotopic implantation model: Human PDAC cells injected directly into the mouse pancreas.
• Genetically engineered mouse models (GEMMs): Mice with endogenous KRAS^G12D and TP53 mutations that spontaneously develop PDAC mimicking human disease.
• Patient-derived xenograft (PDX) models: Human PDAC tumors from patients implanted into immunodeficient mice.

Results were dramatic:

• Complete tumor regression in 100% of treated mice across all models.
• No detectable residual tumor cells by histology or imaging.
• Pancreas tissue appeared histologically normal after treatment.
• No recurrence observed for ≥200 days (≈7 months) post-treatment.
• Minimal toxicity: no significant weight loss, no major organ damage, and good overall tolerability.

These outcomes far exceed typical PDAC mouse studies, where tumor regrowth usually occurs within weeks.Limitations and Translation Challenges to HumansDespite the impressive data, several important caveats remain:

• Mice tolerate higher drug doses and different toxicities than humans.
• Afatinib commonly causes grade 2-3 skin rash and diarrhea in patients.
• PDAC tumors in humans show greater genetic heterogeneity and a more immunosuppressive microenvironment.
• The study used immunodeficient mice in some models, limiting immune system insights.
• Long-term safety of SD36 (a newer PROTAC) is unknown in humans.

CNIO researchers, including Mariano Barbacid and Carmen Guerra, have stated they are optimizing the combination for lower toxicity before pursuing clinical trials.Comparison to Existing and Repurposed TreatmentsSeveral KRAS inhibitors are in development:

• Adagrasib & sotorasib (G12C-specific)
• Emerging pan-KRAS inhibitors (e.g., RMC-6236/Daraxonrasib)
• Combination strategies with SHP2, SOS1, or MEK inhibitors

Repurposed antiparasitics (ivermectin, mebendazole, fenbendazole) have shown modest preclinical growth inhibition (50-80%) in older studies, but none have demonstrated complete, durable regression in orthotopic or PDX pancreatic models comparable to this triple therapy.Social Media Response and Viral SpreadThe study sparked intense discussion on X after rapid amplification across thousands of accounts. Dr. William Makis and others questioned the coordinated promotion, but the underlying science from a respected institution remains credible and mechanistically strong.Implications for Patients and Next StepsThis 2026 study provides strong rationale for advancing multi-pathway KRAS-targeted combinations into early-phase human trials. Patients and caregivers should:

• Consult specialized pancreatic cancer oncologists
• Search ClinicalTrials.gov for trials involving KRAS G12D, panRAS, or STAT3 inhibitors
• Consider participation in precision-medicine programs (e.g., KRAS testing)
• Avoid self-treatment with unproven supplements or repurposed drugs without medical supervision

Frequently Asked Questions (FAQ)Q: Has the triple drug therapy for pancreatic cancer been tested in humans?
A: No. Results are limited to mouse models. Human trials have not started.
Q: What is the current pancreatic cancer survival rate?
A: Overall 5-year survival is ~13%. For localized disease it reaches 44%, but drops to ~3% for distant metastatic disease.
Q: Which specific drugs make up this new pancreatic cancer treatment?
A: Daraxonrasib (KRAS inhibitor), afatinib (EGFR/HER2 inhibitor), and SD36 (STAT3 degrader).
Q: When might this treatment become available?
A: Likely 3–7 years away, depending on successful Phase 1 safety and Phase 2 efficacy trials.
Q: Is this the first triple therapy showing complete regression in PDAC mice?
A: It is among the most impressive reported to date in terms of durability and completeness across multiple models.
Q: Can KRAS G12D pancreatic cancer be targeted?
A: Yes, Daraxonrasib and related agents are specifically designed for G12D and other common variants.ConclusionThe 2026 CNIO triple drug therapy pancreatic cancer study represents one of the most promising preclinical advances in KRAS-driven PDAC research in recent years. Complete tumor eradication and long-term remission in multiple mouse models highlight the power of simultaneous multi-pathway inhibition.

While excitement is justified, rigorous human clinical trials are essential. Continued research into safer combinations and patient stratification will determine whether this approach can finally improve outcomes for one of oncology’s greatest unmet needs.

Combination therapies re-emerge in PDAC research not due to trend or ideology, but as a rational response to the sum of everything that drives resistance: the adaptive rewiring of tumor signaling, survival of cancer stem–like cells, metabolic and epigenetic plasticity, and compensatory feedback loops.

These factors collectively ensure that single-target interventions are rarely sufficient. Whether explored through rigorous oncology research or mirrored conceptually in exploratory drug repurposing frameworks, the lesson is consistent: durable control of pancreatic cancer requires simultaneous, multi-pathway pressure that anticipates tumor adaptation at every level. Integrating these insights — from oncogenic drivers to CSC biology and systemic tumor resilience — provides a unified framework for understanding why combination strategies repeatedly reappear and highlights the pathways most critical for future investigation.

Last updated: February 2026
Related:

• Triple-Drug Combination to Fight Pancreatic Cancer (Oncotarget 2024)
• Advances of HDAC inhibitors in tumor therapy: potential applications through immune modulation (Frontiers in Oncology 2025)