RETRACTED: A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (24)
Vasiliki Liaki
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Sara Barrambana
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Myrto Kostopoulou
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Carmen G. Lechuga
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Elena Zamorano-Dominguez
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Domingo Acosta
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Lucia Morales-Cacho
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Ruth Álvarez
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Pian Sun
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Blanca Rosas-Perez
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Rebeca Barrero
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Silvia Jiménez-Parrado
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Alejandra López-García
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Marta San Roman
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Juan Carlos López-Gil
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Matthias Drosten
Centro de Investigación Biomédica en Red Cancer (CIBERONC)
Bruno Sainz
Centro de Investigación Biomédica en Red Cancer (CIBERONC)
Monica Musteanu
Eduardo Caleiras
Histopathology Unit, Biotechnology Program, Centro Nacional de Investigaciones Oncológicas
Nelson Dusetti
Valeria Poli
Francisco Sánchez-Bueno
Department of Surgery, Hospital Clinico Universitario Virgen de la Arrixaca and Instituto Murciano de Investigación Biomédica
Carmen Guerra
Experimental Oncology Group, Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas
Mariano Barbacid