A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance
Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest cancer survival rates. Recent studies using RAS inhibitors have opened the door to more efficacious therapies, although their beneficial effect is still limited mainly due to the rapid appearance of tumor resistance. Here, we demonstrate that genetic ablation of three independent nodes involved in downstream (RAF1), upstream (EGFR), and orthogonal (STAT3) KRAS signaling pathways leads to complete and permanent regression of orthotopic PDACs induced by KRAS/TP53 mutations. Likewise, a combination of selective inhibitors of KRAS (RMC-6236/daraxonrasib), EGFR family (afatinib), and STAT3 (SD36) induced the complete regression of orthotopic PDAC tumors with no evidence of tumor resistance for over 200 d posttreatment. This combination therapy also led to significant regression of genetically engineered mouse tumors as well as patient-derived tumor xenografts (PDX) in the absence of tumor relapses. Of importance, this combination therapy was well tolerated. In sum, these results should guide the development of new clinical trials that may benefit PDAC patients.
Authors
- Myrto Kostopoulou (ORCID: https://orcid.org/0000-0002-8832-7475)
- Nelson Dusetti (ORCID: https://orcid.org/0000-0002-6161-8483)
- Eduardo Caleiras (ORCID: https://orcid.org/0000-0001-8768-3630)
- Pian Sun
- Lucía Morales-Cacho
- Valeria Poli (ORCID: https://orcid.org/0000-0002-3739-3966)
- Carmen Guerra (ORCID: https://orcid.org/0000-0002-3891-046X)
- Bruno Sáinz (ORCID: https://orcid.org/0000-0003-4829-7651)
- Sara Barrambana (ORCID: https://orcid.org/0000-0003-0200-7129)
- Domingo Acosta (ORCID: https://orcid.org/0009-0009-5434-6078)
- Silvia Jiménez-Parrado
- Juan Carlos López-Gil (ORCID: https://orcid.org/0000-0003-4988-8648)
- Matthias Drosten (ORCID: https://orcid.org/0000-0002-3205-456X)
- Alejandra López-García (ORCID: https://orcid.org/0000-0001-6368-2799)
- Mariano Barbacid (ORCID: https://orcid.org/0000-0002-1480-2624)
- Carmen G. Lechuga
- Mónica Musteanu (ORCID: https://orcid.org/0000-0002-1753-3765)
- Vasiliki Liaki (ORCID: https://orcid.org/0000-0003-3088-5295)
- Francisco Sánchez‐Bueno
- Rafael Barrero
- Marta San Roman
- Ruth Álvarez (ORCID: https://orcid.org/0000-0003-0141-4881)
- Elena Zamorano-Domínguez
- Blanca Rosas-Pérez
Institutions
- Universidad Complutense de Madrid (ES)
- Biotechnology Research Center (IR)
- Instituto de Investigaciones Biomédicas Sols-Morreale (ES)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (ES)
- Instituto Ramón y Cajal de Investigación Sanitaria (ES)
- Centro Nacional de Investigaciones Científicas (CU)
- Institute of Molecular Biology and Biotechnology (BG)
- Centro de Investigación del Cáncer (ES)
- Centre de Recherche en Cancérologie de Marseille (FR)
- Instituto Murciano de Investigación Biosanitaria (ES)
- Hospital Universitario Virgen de la Arrixaca (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- University of Turin (IT)
- Universidad Autónoma de Madrid (ES)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-12-02
- DOI
- https://doi.org/10.1073/pnas.2523039122
- Citations
- 3
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 3.14