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
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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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We thank B. Jime ́nez, M. San Roman, R. Villar, and S. Jime ́nez for excellenttechnical assistance; I. Arago ́n, A. Lo ́pez, F. Dı ́az,and I. Blanco (Animal Facil-ity) for mouse work; G. Visdomine, C. Pen ̃alba, and G. Garaulet (MolecularImaging Unit) for ultrasound studies; P. Vargiu (Transgenic Unit) for help ingenerating theTetO-FlpOstrain; N. Cabrera, A. de Martino (HistopathologyUnit) and M. Morente (Tumor Bank) for histopathological analysis, andC. Blanco and A. Cebria ́(Experimental Therapeutics) for determining theIC50values of gefinitib and erlotinib. Special thanks to J. de la Pen ̃a and E. Ortiz(Servicio de Anatomı ́aPatolo ́gica HCUVA) and T. Escamez and V. Navarro(Biobanco-IMIM) for their help with the PDX tumor models, and to R. Nieto,J.M. Ligo ́s, and M. Montoya (Cytometry Unit, CNIC) for fluorescence-activatedcell sorting analysis of apoptotic cells. This work was supported by grants fromthe European Research Council (advanced grants ERC-AG/250297-RASAHEAD and ERC-AG/695566-THERACAN), from the Spanish Ministry ofEconomy and Competitiveness (SAF2014-59864-R) to M.B. Additional sup-port was also obtained from grants from the Asociacio ́n Espan ̃ola contra elCa ́ncer (GC16173694BARB) to M.B. and B.S., from La Ligue Contre le Cancerto J.I., from the European Research Council (advanced grants ERC-2014-ADG) to M.H., and from the NIH (U54CA193313 and U54CA209997) to R.R.M.T.B was supported by an FPU fellowship from the Spanish Ministry of Edu-cation. C.N. was supported by a Juan de la Cierva Award. M. Djurec waspartially supported by a pre-doctoral fellowship from La Caixa. J.P.-P. wassupported by a Severo Ochoa FPI fellowship from the Spanish Ministry ofEconomy and Competitiveness. M.B. is the recipient of an Endowed Chairfrom the AXA Research Fund.
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Cancer Cell. 2019;35(4):573-587.