Publication: Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF.
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2019-04-15
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Cell Press
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.
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Animals Apoptosis Carcinoma, Pancreatic Ductal Cell Line, Tumor Cell Proliferation ErbB Receptors Erlotinib Hydrochloride Gefitinib Gene Expression Regulation, Neoplastic Humans Mice, 129 Strain Mice, Inbred C57BL Mice, Transgenic Mutation Pancreatic Neoplasms Protein Kinase Inhibitors Proto-Oncogene Proteins c-raf Proto-Oncogene Proteins p21(ras) Signal Transduction Tumor Burden Tumor Suppressor Protein p53 Xenograft Model Antitumor Assays
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Bibliographic citation
Cancer Cell . 2019;35(4):573-587.e6.