A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance
Contributed by Mariano Barbacid; received August 25, 2025; accepted November 3, 2025; reviewed by Anton Berns, Ignacio Garrido-Laguna, and David A. Tuveson
Significance
The development of RAS inhibitors represents a major advance in the treatment of KRAS-driven pancreatic ductal adenocarcinoma (PDAC). RAS(ON) inhibitors such as daraxonrasib (RMC-6236) have led to significant improvements in survival compared to historical data. Unfortunately, the rapid onset of tumor resistance has thwarted their therapeutic benefit. This study describes a triple combination therapy made of daraxonrasib along with afatinib, an irreversible EGFR/HER2 kinase inhibitor and SD36, a selective STAT3 PROTAC that induces the robust regression of experimental PDACs and avoids the onset of tumor resistance. This triple combination is well tolerated in mice. Taken together, these studies open the road to design novel combination therapies that may improve the survival of PDAC patients.
Abstract
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.
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Data, Materials, and Software Availability
All study data are included in the article and/or SI Appendix. No code or sequencing data were generated. For data, material or further information contact mcguerra@cnio.es.
Acknowledgments
We thank R. Villar for excellent technical assistance and I. Aragón, V. Viñas, and I. Blanco (Animal Facility), F. Mulero, G. Visdomine, and G. Medrano (Molecular Imaging Unit), P. Gonzalez (Histopathology Unit), and O. Dominguez (Genomic Unit) of CNIO for their excellent technical support. We also thank J. de la P. and E. Ortiz from the Servicio de Anatomía Patológica of the Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA) (Murcia) and the Biobank of the Instituto Murciano de Investigación Biosanitaria (IMIB) (PT23/00026; Platform ISCIII Biomodels and Biobanks) for providing clinical samples. This work was supported by grants from the CRIS Cancer Foundation, the European Research Council (ERC-AG/695566-THERACAN), the Agencia Estatal de Investigación cofunded with the European Regional Development Fund (ERDF-EU ERDF) (PID2021-124106OB-I00; MCIU/AEI/10.13039/501100011033), and the European Union “NextGenerationEU”/PRTR” (PLEC2022-009255;MCIU/AEI/10.13039/501100011033) to M.B. C.G. and M.B. are recipients of a CIBERONC Fund (CB21/12/00121). Additional funding included grants from the Instituto de Salud Carlos III cofunded by ERDF (PI19/00514), the “Carmen Delgado/Miguel Pérez Mateo Grants of the “Asociación Cancer de Páncreas” to C.G., the Italian Cancer Research Association (AIRC, IG16930), and the Italian Ministry of University and Research (MIUR PRIN 2017) to V.P. M.B. is the recipient of an Endowed Chair from the AXA Research Fund. V.L. was supported by an INPhINIT fellowship from “La Caixa” Foundation (LCF/BQ/DI18/11660011) and a contract from the CRIS Cancer Foundation. S.B. is supported by a PhD scholarship from the Foundation of Science and Technology of Portugal (10.54499/2021.05875.BD). M.K. was supported by an Erasmus+ scholarship for traineeship. L.M.-C. was supported by an FPU fellowship from the Ministerio de Educación. J.C.L-G. is supported by a postdoctoral fellowship from Amigos del CNIO, E.Z.-D. is supported by a FPI fellowship (PRE2022-102952) from the Spanish Ministry of Sciences and Innovation (PID2021-124106OB-I00). P.S. is partially supported by a fellowship from the China Scholarship Council.
Author contributions
V.L., C.G., and M.B. designed research; V.L., S.B., M.K., C.G.L., E.Z.-D., D.A., L.M.-C., P.S., B.R.-P., R.B., S.J.-P., A.L.-G., M.S.R., and J.C.L.-G. performed research; B.S., N.D., V.P., and F.S.-B. contributed new reagents/analytic tools; V.L., S.B., R.A., M.D., M.M., E.C., and C.G. analyzed data; M.D. and M.M. provided critical input; and V.L., S.B., C.G., and M.B. wrote the paper.
Competing interests
V.L. and C.G. declare an International Patent Application PCT/EP2024/052345 and a European Patent Application No. 23382078.6 entitled “Triple combined therapy inhibiting EGFR, RAF1 and STAT3 against pancreatic ductal adenocarcinoma.” V.L., C.G., and M.B. declare a European Patent Application No. 25382815.6. entitled “Novel Therapy.” Reviewer I.G.-L. notes the following: “I am a principal investigator in the first-in-human trial with RMC-6236 (Daraxonrasib) as well as PI in the randomized phase 3 trial (RASOLUTE-302) comparing RMC-6236 to standard chemotherapy in patients with metastatic pancreatic cancer in the second line. I have received consulting fees for participating in advisory boards for Revolution Medicine.”.
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References
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R. L. Siegel, K. D. Miller, N. S. Wagle, A. Jemal, Cancer statistics, 2023. CA Cancer J. Clin. 73, 17–48 (2023).
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Copyright © 2025 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Data, Materials, and Software Availability
All study data are included in the article and/or SI Appendix. No code or sequencing data were generated. For data, material or further information contact mcguerra@cnio.es.
Submission history
Received: August 25, 2025
Accepted: November 3, 2025
Published online: December 2, 2025
Published in issue: December 9, 2025
Keywords
Acknowledgments
We thank R. Villar for excellent technical assistance and I. Aragón, V. Viñas, and I. Blanco (Animal Facility), F. Mulero, G. Visdomine, and G. Medrano (Molecular Imaging Unit), P. Gonzalez (Histopathology Unit), and O. Dominguez (Genomic Unit) of CNIO for their excellent technical support. We also thank J. de la P. and E. Ortiz from the Servicio de Anatomía Patológica of the Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA) (Murcia) and the Biobank of the Instituto Murciano de Investigación Biosanitaria (IMIB) (PT23/00026; Platform ISCIII Biomodels and Biobanks) for providing clinical samples. This work was supported by grants from the CRIS Cancer Foundation, the European Research Council (ERC-AG/695566-THERACAN), the Agencia Estatal de Investigación cofunded with the European Regional Development Fund (ERDF-EU ERDF) (PID2021-124106OB-I00; MCIU/AEI/10.13039/501100011033), and the European Union “NextGenerationEU”/PRTR” (PLEC2022-009255;MCIU/AEI/10.13039/501100011033) to M.B. C.G. and M.B. are recipients of a CIBERONC Fund (CB21/12/00121). Additional funding included grants from the Instituto de Salud Carlos III cofunded by ERDF (PI19/00514), the “Carmen Delgado/Miguel Pérez Mateo Grants of the “Asociación Cancer de Páncreas” to C.G., the Italian Cancer Research Association (AIRC, IG16930), and the Italian Ministry of University and Research (MIUR PRIN 2017) to V.P. M.B. is the recipient of an Endowed Chair from the AXA Research Fund. V.L. was supported by an INPhINIT fellowship from “La Caixa” Foundation (LCF/BQ/DI18/11660011) and a contract from the CRIS Cancer Foundation. S.B. is supported by a PhD scholarship from the Foundation of Science and Technology of Portugal (10.54499/2021.05875.BD). M.K. was supported by an Erasmus+ scholarship for traineeship. L.M.-C. was supported by an FPU fellowship from the Ministerio de Educación. J.C.L-G. is supported by a postdoctoral fellowship from Amigos del CNIO, E.Z.-D. is supported by a FPI fellowship (PRE2022-102952) from the Spanish Ministry of Sciences and Innovation (PID2021-124106OB-I00). P.S. is partially supported by a fellowship from the China Scholarship Council.
Author contributions
V.L., C.G., and M.B. designed research; V.L., S.B., M.K., C.G.L., E.Z.-D., D.A., L.M.-C., P.S., B.R.-P., R.B., S.J.-P., A.L.-G., M.S.R., and J.C.L.-G. performed research; B.S., N.D., V.P., and F.S.-B. contributed new reagents/analytic tools; V.L., S.B., R.A., M.D., M.M., E.C., and C.G. analyzed data; M.D. and M.M. provided critical input; and V.L., S.B., C.G., and M.B. wrote the paper.
Competing interests
V.L. and C.G. declare an International Patent Application PCT/EP2024/052345 and a European Patent Application No. 23382078.6 entitled “Triple combined therapy inhibiting EGFR, RAF1 and STAT3 against pancreatic ductal adenocarcinoma.” V.L., C.G., and M.B. declare a European Patent Application No. 25382815.6. entitled “Novel Therapy.” Reviewer I.G.-L. notes the following: “I am a principal investigator in the first-in-human trial with RMC-6236 (Daraxonrasib) as well as PI in the randomized phase 3 trial (RASOLUTE-302) comparing RMC-6236 to standard chemotherapy in patients with metastatic pancreatic cancer in the second line. I have received consulting fees for participating in advisory boards for Revolution Medicine.”.
Notes
Reviewers: A.B., Netherlands Cancer Institute; I.G.-L., Professor of Oncology at the University of Utah School of Medicine and Director of the Phase I Program at Huntsman Cancer Institute; and D.A.T., Cold Spring Harbor Laboratory Cancer Center.
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A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance, Proc. Natl. Acad. Sci. U.S.A.
122 (49) e2523039122,
https://doi.org/10.1073/pnas.2523039122
(2025).
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