By: Gayatri Chitralekhaji
Spain’s National Cancer Research Centre (CNIO) has reported a striking laboratory advance against pancreatic cancer. In a study published this week in PNAS, Dr. Mariano Barbacid’s team demonstrated that a three‐drug regimen eradicated pancreatic tumours in mice and prevented relapse with “no significant side effects”. The approach works by blocking the KRAS pathway, mutated in roughly 90% of pancreatic cancers, at three distinct points, forestalling the drug resistance that normally lets tumours rebound. In tests on three different mouse models of pancreatic ductal adenocarcinoma (PDAC), all treated tumours regressed completely and did not recur for over 200 days. Barbacid’s group and its co-authors say their findings “set the course” for designing new combination therapies and future clinical trials.
Pancreatic cancer is notoriously lethal, often dubbed among the most aggressive tumours with a dismal outlook. Globally, about 510,000 people were diagnosed in 2022 and nearly as many, 467,000 died of the disease. Late detection is common as there is no effective screening test and standard treatments such as surgery and chemotherapy have yielded little improvement. The five-year survival rate worldwide hovers near 10%. In Spain alone, some 10,300 new cases occur each year and fewer than one in ten patients lives beyond five years. Researchers and oncologists have long agreed that pancreatic cancer constitutes an urgent unmet need, making any advance eagerly watched.
Targeting KRAS from three angles
The new therapy builds on the biology of PDAC, mutations in the gene KRAS drive the cancer’s growth in roughly 90% of cases. KRAS was long considered “undruggable”, but since 2021 the first targeted KRAS inhibitors have reached the clinic. Unfortunately these agents, for example, drugs like adagrasib and sotorasib that hit KRAS G12C mutations, have shown only modest benefit in pancreatic cancer, because tumours quickly evolve resistance. In effect, blocking KRAS at a single point is usually not enough, the cancer finds a detour.
Barbacid’s team therefore adopted a multi-pronged strategy. Working in mice, they genetically knocked out three key nodes of the KRAS signalling network, a downstream kinase RAF1, the upstream EGFR receptors, and the parallel STAT3 survival pathways, and found that simultaneous blockade caused tumours to vanish permanently. As the CNIO press release put it, it is “harder for a beam to break if it is fixed at three points, rather than just one” and indeed the genetically engineered tumours disappeared completely when all three are cut. In practice this was mimicked pharmacologically by combining three drugs. The triple cocktail was 1) Daraxonrasib (RMC-6236), a novel, direct KRAS(ON) inhibitor designed to hit multiple KRAS mutants simultaneously; 2) Afatinib, an approved EGFR-family tyrosine-kinase inhibitor also used in some lung cancers; and 3) SD36, a selective protein degrader that targets the STAT3 transcription factor.
Each drug hits one prong of the pathway, RAF/MAPK via KRAS, EGFR family receptors, and STAT3-mediated survival signals. By “attacking the cancer from three directions simultaneously,” as one commentator notes, the team stopped the tumour’s usual escape routes.
Complete tumour regression in mice
When applied to mice implanted with human-like PDAC tumours including genetically engineered models and patient‐ derived xenografts, the triple regimen caused massive and durable tumour shrinkage. In all three animal models, tumours fully disappeared under treatment, and none showed any relapse during extended follow-up. Remarkably, the therapy was well tolerated by the animals. No significant weight loss or organ toxicity was seen, and normal cells appeared unharmed, implying a wide safety margin in mice. The combination drove “complete and permanent regression” of pancreatic tumours in mice.
Chinese-American chemist Simon Maechling, writing on social media, cautioned that “Mice are a filter – not a finish line,” but he conceded the results are impressive as full tumour regression without relapse constitutes life-saving progress. Spanish officials and media have likewise hailed the advance. Spain’s Embassy in London tweeted that Barbacid’s group had achieved the “complete and permanent disappearance of pancreatic cancer in experimental models,” a discovery “that could make a difference in the fight against this disease”.
A cautious path to patients
Despite the excitement, the researchers themselves insist this is not yet a cure for patients. The CNIO paper and press statement put to stress that human trials are still many steps away. Barbacid notes flatly, “We are not yet in a position to carry out clinical trials with this triple therapy”. The team and outside experts point out that triple‐drug regimens can be difficult to translate. Dosages must be optimised, off-target effects assessed, and regulators will demand rigorous safety data, all of which will take time.
Moreover, pancreatic tumours in mice are far simpler than the real thing in people. Past “cures” in rodent models have often failed in humans. One expert warns that while the CNIO result “comes from the Spanish National Cancer Research Centre and full tumour regression is impressive, here’s what it actually means: this approach is now good enough to risk years, trials, and millions of euros on,” not that “Cancer is solved”. Thus, the finding is yet only a breakthrough in the lab, not an instant patient treatment.
Realistically, observers expect years of development ahead. Even optimists reckon it could be a decade before any human benefits are seen as one analysis notes that under a normal clinical timeline, definitive results for patients might not emerge for 8-10 years at the earliest. In the meantime, the CNIO study will likely spur pharmaceutical and biotech interest. Several companies are already developing the individual components such as Revolution Medicines testing daraxonrasib in PDAC trials, and the new data suggest combining them could be worthwhile. There may be investor and R&D appetite for multi-target trials in pancreatic cancer going forward.
The broader challenge
This advance must be seen in the context of a very tough cancer. Decades of research have yielded scant progress in PDAC, only in 2021 did the first targeted KRAS inhibitor reach patients, and even that gave only a few more months of control at best. Tumours usually evolve resistance within weeks or months. Immunotherapy that has revolutionised other cancers has so far been mostly ineffective in PDAC. Combined with the fact that pancreatic tumours are often diagnosed too late for surgery, the result has been stagnation, annual mortality nearly equals incidence, and five-year survival has crept up only marginally from about 5% a generation ago to 10% today.
If the triple-drug approach can eventually be adapted to humans, it would represent a paradigm shift. By shutting down KRAS signalling at multiple points, it might finally overcome the pattern of transient responses. That could transform a near-certain killer into a chronically manageable disease. But on the way there lies a series of daunting steps from finding the right drug analogs and doses for people, to designing complex clinical trials of three‐drug regimens. Nevertheless, experts say the new results “open the way to design new combination therapies that can improve survival” in pancreatic ductal adenocarcinoma. For patients and investors alike, the finding has at least injected fresh hope into a field where hope has been in short supply.
In preclinical models, the CNIO team’s triple‐drug cocktail (KRAS inhibitor + EGFR inhibitor + STAT3 degrader) eliminated pancreatic tumours in mice with no relapse for months. The regimen was well tolerated. The strategy works by attacking the KRAS oncogene pathway at three nodes (RAF1/MAPK downstream, EGFR upstream, and parallel STAT3) to prevent resistance. However, human trials are still many years off, the researchers stress that while the results are unprecedented, this is a path to future treatments, not an immediate cure.