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

María Teresa, Blasco, Carolina, Navas, Guillermo, Martín-Serrano, Osvaldo, Graña-Castro, Carmen G., Lechuga, Laura, Martín-Díaz, Magdolna, Djurec, Jing, Li, Lucia, Morales-Cacho, Laura, Esteban-Burgos, Javier, Perales-Patón, Emilie, Bousquet-Mur, Eva, Castellano, Harrys K.C., Jacob, Lavinia, Cabras, Monica, Musteanu, Matthias, Drosten, Sagrario, Ortega, Francisca, Mulero, Bruno, Sainz, Nelson, Dusetti, Juan, Iovanna, Francisco, Sánchez-Bueno, Manuel, Hidalgo, Hossein, Khiabanian, Raul, Rabadán, Fátima, Al-Shahrour, Carmen, Guerra, Mariano, Barbacid

Cancer Cell | 2019

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 geneti- cally engineered mice. Moreover, systemic elimination of these targets induces toxicities that are well toler- ated. 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.

https://linkinghub.elsevier.com/retrieve/pii/S1535610819301114