In a striking advance against one of medicine’s most formidable foes, researchers at Spain’s National Cancer Research Centre (CNIO) have eradicated pancreatic ductal adenocarcinoma tumors in multiple mouse models using a three-drug regimen that blocks cancer’s survival pathways at key chokepoints. Published in the Proceedings of the National Academy of Sciences ( PNAS ), the study led by Mariano Barbacid demonstrates complete, durable tumor regression without relapse or significant toxicity, a feat long elusive in preclinical pancreatic cancer research.

The therapy combines daraxonrasib, an experimental KRAS(ON) inhibitor; afatinib, an approved pan-ERBB inhibitor used in lung cancer; and SD-36, a selective STAT3 protein degrader. This trio targets the KRAS oncogene—mutated in over 90% of cases—while sealing off adaptive resistance routes via EGFR/HER2 and STAT3 feedback loops. ‘This study describes a triple combination therapy…that induces the robust regression of experimental PDACs and avoids the onset of tumor resistance. This triple combination is well tolerated in mice,’ the authors state in the paper.

Tested across three rigorous models—genetically engineered mice born with cancer-causing mutations, orthotopic implants of human pancreatic tissue, and surgical implantation of patient-derived cancer cells—the regimen achieved total tumor elimination. In one cohort, 16 of 18 immunocompromised mice showed complete regression, with no recurrence observed within monitoring periods exceeding 200 days in some cases. Tumors vanished permanently, even after treatment cessation.

Decoding KRAS’s Elusive Grip

Pancreatic ductal adenocarcinoma claims over 10,300 lives annually in Spain alone, with a five-year survival rate below 10%, according to CNIO data. Globally, the disease’s lethality stems from late diagnosis and rapid resistance to therapies. KRAS mutations drive proliferation like a jammed accelerator, but single inhibitors fail as tumors reroute signals through bypass pathways. Barbacid’s group, leveraging decades of KRAS expertise—Barbacid isolated the first human oncogene in 1982—mapped these escapes using genetically modified mice.

Prior KRAS blockers, approved since 2021, lose efficacy within months. The CNIO approach fortifies the attack: daraxonrasib halts the primary signal, afatinib blocks upstream EGFR/HER2 reactivation, and SD-36 dismantles STAT3-mediated survival under stress. ‘It is more difficult for a beam to break if it is fixed to the ceiling in three places rather than only one,’ Barbacid analogized in a CNIO release .

Healthy young mice tolerated the drugs well, unlike frail human patients, but low toxicity signals feasibility. ‘These studies open a path to designing new combination therapies that can improve survival for patients with pancreatic ductal adenocarcinoma,’ the team writes, urging clinical exploration.

Rigorous Models Mimic Human Disease

First authors Vasiliki Liaki and Sara Barrambana, with co-lead Carmen Guerra, employed models closely approximating human pathology. Genetically engineered mice develop spontaneous tumors mirroring progression from inception. Patient-derived xenografts preserve human stroma and heterogeneity. Orthotopic implants replicate anatomical invasion. Across all, tumors regressed fully, with no resistant clones emerging—a rarity in oncology.

The Daily Mail ( Jan. 30, 2026 ) highlighted the Embassy of Spain in the UK’s endorsement: ‘A team of scientists from the Spanish Cancer Research Centre, led by the renowned Dr Mariano Barbacid, has achieved the complete and permanent disappearance of pancreatic cancer in experimental models.’

NDTV ( Jan. 29, 2026 ) noted the absence of major side effects, echoing Business Standard’s ( Jan. 29, 2026 ) report of tumors vanishing without severe toxicity by attacking the KRAS pathway comprehensively.

Resistance: The Achilles’ Heel Overcome

Cancer’s adaptability dooms monotherapies; KRAS inhibition prompts EGFR rebound and STAT3 activation, fueling relapse. The triple hit preempts this rewiring. India Today’s ( Jan. 29, 2026 ) decode explains: ‘Cancer is clever… When one pathway is blocked, tumours often find alternative routes.’ Here, all are severed simultaneously.

On X, @Bohrium_AI4S detailed: ‘MRTX1133 – inhibits KRAS G12D… Afatinib – blocks EGFR-mediated bypass… SD-36 – degrades STAT3.’ While specifics vary slightly across reports (e.g., RMC-6236 or daraxonrasib as KRAS blockers), the strategy aligns. Euronews ( Jan. 28, 2026 ) confirmed triple therapy’s tumor elimination in mice.

IBTimes UK ( Jan. 30, 2026 ) captured social buzz: ‘Tumours shrank completely and did not grow back for more than 200 days.’

Barbacid’s Odyssey in Oncology

Mariano Barbacid, CNIO’s Experimental Oncology Group head, pioneered RAS oncogene discovery, shaping targeted therapy. After industry stints at Bristol Myers Squibb, he founded CNIO. The Economic Times ( Jan. 29, 2026 ) profiled: ‘Combines an existing lung cancer drug with a protein degrader.’

Caution tempers optimism. ‘We are not yet in a position to carry out clinical trials with this triple therapy,’ Barbacid told CNIO. Human hurdles include dosing, patient frailty, and stroma barriers absent in mice. Translation rates from rodents hover below 10% historically.

Yet, the paper asserts: ‘These results point the way for developing new clinical trials.’ X users like @aakashgupta emphasized Barbacid’s legacy: ‘The man who discovered human oncogenes in 1982 may have just figured out how to eliminate the cancer those genes cause.’

Path to Patients: Trials on Horizon

Optimizing for clinics won’t be swift—regulatory nods, combo safety data needed. Daraxonrasib-like agents advance in trials; afatinib is approved. If validated, survival could leap from months. Spain’s 10,500 yearly UK cases ( Daily Mail ) underscore urgency—over 50% die within three months.

X reactions mix hope and hype. @ever_e_mann shared personal loss: ‘My dad died from pancreatic cancer 8 months after diagnosis.’ @PamphletsY’s clip amassed millions of views, sparking ‘protect him’ memes amid birthmark trolls, per News18.

For industry insiders, this validates multi-pathway blockade. As Barbacid’s team charts translation, the field eyes combos blending KRAS inhibitors with degrader tech, potentially reshaping pancreatic cancer’s grim equation.