A groundbreaking study from Spain’s National Cancer Research Centre (CNIO) unveils a revolutionary approach in the fight against pancreatic cancer, promising to change the landscape of treatment for this notoriously lethal disease. Pancreatic ductal adenocarcinoma (PDAC), the most prevalent form of pancreatic cancer, remains one of the deadliest cancers globally, with a five-year survival rate that stubbornly lingers below 10%. This grim prognosis is largely due to the rapid development of resistance to current therapeutics and late-stage detection. However, a novel triple combination therapy tested in mouse models now demonstrates complete and durable tumor eradication without the emergence of resistance or significant toxicity, heralding a new era in oncology.
The core challenge in treating PDAC has long been its molecular complexity and the resilience of its tumors, which evolve rapidly to evade therapeutic interventions. Traditional chemotherapies have yielded limited success over decades, and recent advancements targeting the KRAS oncogene, mutated in approximately 90% of pancreatic cancers, have shown promising yet transient effects. KRAS inhibitors initially arrest tumor growth but soon face the obstacle of adaptive resistance, causing therapeutic efficacy to wane within months. The CNIO team, led by Mariano Barbacid, has tackled this issue with a strategic innovation: simultaneously targeting three critical nodes within the KRAS signaling cascade, thereby creating a triad of inhibition that hampers the tumor’s ability to compensate or bypass the blockade.
This triple therapy approach is conceptually akin to reinforcing a fragile beam at three points instead of one, dramatically reducing the likelihood of structural failure. By genetically ablating three molecular targets downstream of KRAS in murine models, the researchers observed near-complete regression of pancreatic tumors, with remarkably enduring results and an absence of relapse. This contrasts starkly with prior single-agent therapies, where the tumor swiftly adapts through alternate pathways or mutations. Importantly, these genetic insights have been translated into pharmacological intervention, coupling an experimental KRAS inhibitor, daraxonrasib (also known as RMC-6236), with afatinib, an EGFR inhibitor approved for lung adenocarcinoma, alongside a STAT3 protein degrader, SD36. This triple regimen demonstrated sustained tumor regression in diverse mouse models, marking a significant stride toward clinical applicability.
The sophisticated design of this therapy reflects a deep understanding of PDAC’s molecular circuitry. KRAS mutations drive tumorigenesis through several downstream effectors, including the RAF-MEK-ERK pathway, the EGFR axis, and STAT3, a transcription factor promoting oncogenic inflammation and survival. Individually inhibiting these components has proved insufficient due to compensatory signaling, but their concurrent blockade yields a synergistic shutdown of tumor sustenance. The researchers meticulously confirmed that this multi-pronged inhibition not only induces tumor cell death but also impedes resistance mechanisms, a notorious barrier in PDAC therapies. Crucially, the treatment was well tolerated in mice, alleviating concerns about potential systemic toxicity from targeting multiple pathways.
While the implications of these findings are profound, the path toward human clinical trials remains cautious. Mariano Barbacid underscores that despite the unprecedented preclinical success, further optimization and safety evaluations are imperative before embarking on trials involving patients. The complexity of translating combination therapies requires meticulous pharmacokinetic and pharmacodynamic assessments, dosage calibrations, and careful monitoring to circumvent adverse effects. Nonetheless, these results open an optimistic avenue for devising next-generation treatments that could significantly extend survival for PDAC patients, who currently face dismal prognoses with few therapeutic options.
The scientific community has taken note of this breakthrough, which appears in the prestigious Proceedings of the National Academy of Sciences (PNAS). The article, co-led by Carmen Guerra and with first authors Vasiliki Liaki and Sara Barrambana, meticulously details the experimental design, molecular rationale, and therapeutic outcomes that underpin this innovative strategy. The study represents a culmination of decades of foundational work elucidating KRAS-driven oncogenesis and overcoming the challenge of tumor resistance, demonstrating how targeted molecular therapies can be precisely tailored to the biology of aggressive cancers.
Pancreatic cancer remains a formidable opponent, with over 10,300 new cases diagnosed annually in Spain alone. The aggressive nature of the disease, combined with silent symptomatology, often results in late detection after metastasis, complicating treatment efforts. The CNIO team’s pioneering work addresses these hurdles by developing a mechanism-based therapy grounded in molecular oncology principles, leveraging recent advances in drug development, and repurposing agents like afatinib in novel contexts. This integrative approach exemplifies modern cancer therapeutics, where combination regimens are designed based on tumor biology rather than empirical drug combinations.
The research also highlights the importance of collaborative funding and resource allocation to tackle challenging cancers. Supported by Fundación CRIS Contra el Cáncer, the European Research Council, and multiple national and international agencies, this project underscores how strategic investment in cutting-edge oncology research can yield transformative clinical prospects. The study’s authors anticipate that continuous refinement of this triple therapy, alongside biomarker development to monitor efficacy and resistance, will pave the way for clinical translation within a foreseeable timeframe.
Notably, the study includes a conflict-of-interest statement disclosing patent applications related to the triple therapy and involvement of some researchers in clinical trials with daraxonrasib, ensuring transparency in the scientific discourse. These patent filings indicate a forward-looking vision to commercialize and disseminate the therapy pending successful clinical validation. Concurrent trials in pancreatic cancer with KRAS inhibitors will provide invaluable comparative data, informing future therapeutic strategies and potential combination regimens.
In summary, this landmark study from CNIO offers a beacon of hope in the battle against pancreatic cancer. By ingeniously circumventing the adaptive resistance mechanisms of PDAC tumors through a targeted triple therapy, the researchers have demonstrated a blueprint for durable tumor control. This work not only enhances our molecular understanding of KRAS-driven cancers but also sets a compelling precedent for the development of combination therapies in oncology. The transition from bench to bedside, while necessitating rigorous validation, may ultimately deliver improved outcomes for patients afflicted by this devastating disease.
Subject of Research: Animals
Article Title: A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance
News Publication Date: 2-Dec-2025
Web References:
https://www.pnas.org/doi/10.1073/pnas.2523039122
References:
Barbacid, M., Guerra, C., Liaki, V., Barrambana, S., et al. (2025). A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance. Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2523039122.
Image Credits: CNIO Molecular Oncology Group, Credit: MadMoviex. CNIO
Keywords: Pancreatic cancer, Tumor regression, Oncology, Drug resistance, Drug targets
