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Cancer Cell. 2019 Apr 15;35(4):573-587.e6. doi: 10.1016/j.ccell.2019.03.002. Epub 2019 Apr 8.

Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF.

Author information

1
Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain.
2
Bioinformatics Unit, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain.
3
Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain.
4
Transgenic Unit, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain.
5
Molecular Imaging Unit, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain.
6
Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain; Department of Biochemistry, School of Medicine, Autonomous University of Madrid, 28018 Madrid, Spain.
7
Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm U1068, CNRS UMR 7258, Aix-Marseille Université et Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, 163, Avenue de Luminy, 13288 Marseille, France.
8
Department of Surgery, Clinical University Hospital 'Virgen Arrixaca' - Murcian Institute of Biomedical Investigation (IMIB), 30120 Murcia, Spain.
9
Rosenberg Clinical Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
10
Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
11
Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain. Electronic address: mcguerra@cnio.es.
12
Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain. Electronic address: mbarbacid@cnio.es.

Abstract

Five-year survival for pancreatic ductal adenocarcinoma (PDAC) patients remains below 7% due to the lack of effective treatments. Here, we report that combined ablation of EGFR and c-RAF expression results in complete regression of a significant percentage of PDAC tumors driven by Kras/Trp53 mutations in genetically engineered mice. Moreover, systemic elimination of these targets induces toxicities that are well tolerated. Response to this targeted therapy correlates with transcriptional profiles that resemble those observed in human PDACs. Finally, inhibition of EGFR and c-RAF expression effectively blocked tumor progression in nine independent patient-derived xenografts carrying KRAS and TP53 mutations. These results open the door to the development of targeted therapies for PDAC patients.

KEYWORDS:

Cdk4; EGFR; Erlotinib; PDX tumor models; Pancreatic cancer; c-Raf; therapeutic mouse models; transcriptional profiles; tumor regression

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