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Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF.
Cancer Cell ( IF 48.8 ) Pub Date : 2019-04-08 , DOI: 10.1016/j.ccell.2019.03.002 María Teresa Blasco 1 , Carolina Navas 1 , Guillermo Martín-Serrano 2 , Osvaldo Graña-Castro 2 , Carmen G Lechuga 1 , Laura Martín-Díaz 3 , Magdolna Djurec 3 , Jing Li 1 , Lucia Morales-Cacho 1 , Laura Esteban-Burgos 1 , Javier Perales-Patón 2 , Emilie Bousquet-Mur 3 , Eva Castellano 3 , Harrys K C Jacob 3 , Lavinia Cabras 3 , Monica Musteanu 1 , Matthias Drosten 1 , Sagrario Ortega 4 , Francisca Mulero 5 , Bruno Sainz 6 , Nelson Dusetti 7 , Juan Iovanna 7 , Francisco Sánchez-Bueno 8 , Manuel Hidalgo 9 , Hossein Khiabanian 10 , Raul Rabadán 10 , Fátima Al-Shahrour 2 , Carmen Guerra 1 , Mariano Barbacid 1
Cancer Cell ( IF 48.8 ) Pub Date : 2019-04-08 , DOI: 10.1016/j.ccell.2019.03.002 María Teresa Blasco 1 , Carolina Navas 1 , Guillermo Martín-Serrano 2 , Osvaldo Graña-Castro 2 , Carmen G Lechuga 1 , Laura Martín-Díaz 3 , Magdolna Djurec 3 , Jing Li 1 , Lucia Morales-Cacho 1 , Laura Esteban-Burgos 1 , Javier Perales-Patón 2 , Emilie Bousquet-Mur 3 , Eva Castellano 3 , Harrys K C Jacob 3 , Lavinia Cabras 3 , Monica Musteanu 1 , Matthias Drosten 1 , Sagrario Ortega 4 , Francisca Mulero 5 , Bruno Sainz 6 , Nelson Dusetti 7 , Juan Iovanna 7 , Francisco Sánchez-Bueno 8 , Manuel Hidalgo 9 , Hossein Khiabanian 10 , Raul Rabadán 10 , Fátima Al-Shahrour 2 , Carmen Guerra 1 , Mariano Barbacid 1
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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.
中文翻译：
联合抑制 EGFR 和 C-RAF 后晚期胰腺导管腺癌的完全消退。
由于缺乏有效的治疗方法，胰腺导管腺癌 (PDAC) 患者的五年生存率仍低于 7%。在这里，我们报告了 EGFR 和 c-RAF 表达的联合消融导致基因工程小鼠中由 Kras/Trp53 突变驱动的很大比例的 PDAC 肿瘤完全消退。此外，系统性消除这些靶标会引起耐受性良好的毒性。对这种靶向治疗的反应与转录谱相关，类似于在人类 PDAC 中观察到的转录谱。最后，抑制 EGFR 和 c-RAF 表达有效地阻止了九个独立的患者来源的携带 KRAS 和 TP53 突变的异种移植物的肿瘤进展。这些结果为开发针对 PDAC 患者的靶向疗法打开了大门。
更新日期：2019-04-08
中文翻译：
联合抑制 EGFR 和 C-RAF 后晚期胰腺导管腺癌的完全消退。
由于缺乏有效的治疗方法，胰腺导管腺癌 (PDAC) 患者的五年生存率仍低于 7%。在这里，我们报告了 EGFR 和 c-RAF 表达的联合消融导致基因工程小鼠中由 Kras/Trp53 突变驱动的很大比例的 PDAC 肿瘤完全消退。此外，系统性消除这些靶标会引起耐受性良好的毒性。对这种靶向治疗的反应与转录谱相关，类似于在人类 PDAC 中观察到的转录谱。最后，抑制 EGFR 和 c-RAF 表达有效地阻止了九个独立的患者来源的携带 KRAS 和 TP53 突变的异种移植物的肿瘤进展。这些结果为开发针对 PDAC 患者的靶向疗法打开了大门。
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