Preclinical findings show antitumour activity of triple KRAS inhibition in mouse models, but it will take years of rigorous research to assess its clinical efficacy in oncology patients
“One patient had reported to me the news that they had cured pancreatic cancer with three new drugs. Another one was asking specifically how he could get access to this treatment, even off-label since these drugs are already in the clinic. I had to explain that this combination has not yet been tested in humans for dose-finding and/or safety.” What happened to Dr Rachna T. Shroff, of the University of Arizona Cancer Center, Tucson, AZ, USA, and member of the ESMO Communication Committee, was shared by many other oncology professionals over the last few days, after a preclinical research study published in Proceeding of the National Academy of Sciences (PNAS) hit the news globally (Proc Natl Acad Sci U S A. 2025 Dec 9;122(49):e2523039122 ).
The team of the Experimental Oncology Group at the National Cancer Research Centre (CNIO) in Madrid, Spain, led by Prof. Mariano Barbacid, investigated the antitumour effect of targeting three nodes that control KRAS signalling pathways - Raf1, Egfr, and Stat3 – applying a triple-combination therapy of daraxonrasib, a novel RAS(ON) inhibitor, the EGFR-tyrosine kinase inhibitor (TKI) afatinib, and SD36, a selective proteolysis targeting chimera (PROTAC) degrader of STAT3 protein, in vitro and in genetically engineered mouse (GEM) models of pancreatic ductal adenocarcinoma (PDAC).
Tumour-bearing mice treated with the novel treatment underwent rapid apoptotic cell death that resulted in complete tumour regressions and remained tumour-free for over 200 days post-treatment, suggesting a potential therapeutic impact overcoming the onset of tumour resistance.
These are exciting news, since the results may represent a significant step toward understanding therapeutic vulnerabilities of pancreatic cancer. But they are not yet applicable to patient care. “Laboratory work cannot be directly translated into clinical reality without running rigorously controlled clinical trials,” cautions Dr Ben Westphalen, University Hospital LMU Munich, Germany, Chair of the ESMO Precision Oncology Task Force. “In pancreatic cancer, we have seen promising results in model systems in the past that, however, led to unfavourable results in patients, which were then recapitulated in the laboratory,” he says. He specifically recalls the case of the Hedgehog cellular signalling pathway, whose inhibition appeared to be a promising strategy to improve the delivery and efficacy of gemcitabine in mouse models of PDAC years ago (Science. 2009 Jun 12;324(5933):1457-61). However, subsequent research did not confirm those preclinical findings in phase I studies (J Clin Oncol. 2015 Dec 20;33(36):4284-92 ; Pancreas. 2016 Mar;45(3):370-5 ) and led to further in vitro and murine model investigations to assess the underlying causes of that failure (Cancer Cell. 2014 Jun 16;25(6):735-47 ; Cancer Cell. 2014 Jun 16;25(6):719-34 ).
Moreover, what needs to be proven is not only that the novel triple combination therapy is effective in people with PDAC, but also what potential side-effects it may carry in humans. “We already know that the combination of EGFR and KRAS targeting agents alone has overlapping toxicities, and the addition of the STAT3 PROTAC may introduce further adverse effects,” adds Shroff.
The excitement surrounding the Spanish study findings is partly driven by the dismal prognosis of PDAC, which has remained mostly unchanged over the last 20 years (Lancet. 2025 Apr 5;405(10485):1182-1202). Ever since KRAS recently became a ‘druggable’ oncogenic driver, the number of selective inhibitors has been growing steadily, offering new potential opportunities to patients, whose treatment relies today on gemcitabine, either alone or in combination with nab-paclitaxel, and 5-fluoracil (F) based regimens such as FOLFIRINOX and nalIRIFOX with limited benefits (Ann of Oncol, 2023;Vol 34, Issue 11, 987-1002). However, toxicity and primary or acquired resistance are major challenges to the clinical use of these targeted (Genes Dev. 2025 Jan 7;39(1-2):132-162).
“In this disease, with a critical unmet medical need, the hope for innovative and effective RAS-inhibitors is especially high,” highlights Westphalen. “Parallel to the clinical development of RAS-inhibitors, scientists have now taken up the task of understanding the effects of these agents and emerging mechanisms of resistance, and how to eventually overcome them.” It is against this backdrop that the findings observed in mice by the Spanish team should be assessed, and whether RAS inhibition will be a true breakthrough in this difficult-to-treat disease is uncertain. “This translational research will be critical to push the field forward as the results obtained in model systems will help to inform the clinical development of these novel drugs in patients with cancer and how they can be employed most effectively,” he concludes.
