c-RAF Ablation Induces Regression of Advanced Kras/Trp53 Mutant Lung Adenocarcinomas by a Mechanism Independent of MAPK Signaling

被引：93

作者：

Sanclemente, Manuel ^{[1
]}

Francoz, Sarah ^{[1
,3
]}

Esteban-Burgos, Laura ^{[1
]}

Bousquet-Mur, Emilie ^{[1
,4
]}

Djurec, Magdolna ^{[1
]}

Lopez-Casas, Pedro P. ^{[2
]}

Hidalgo, Manuel ^{[2
,5
]}

Guerra, Carmen ^{[1
]}

Drosten, Matthias ^{[1
]}

Musteanu, Monica ^{[1
]}

Barbacid, Mariano ^{[1
]}

机构：

[1] CNIO, Mol Oncol Program, Madrid 28029, Spain

[2] CNIO, Clin Res Program, Madrid 28029, Spain

[3] CNIC, Cell & Dev Biol Area, Madrid 28029, Spain

[4] IRCM, Oncogen Pathways Lung Canc, F-34298 Montpellier, France

[5] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA

来源：

CANCER CELL | 2018年 / 33卷 / 02期

基金：

欧洲研究理事会;

关键词：

B-RAF; CANCER; EXPRESSION; APOPTOSIS; ONCOGENE; LEADS;

D O I：

10.1016/j.ccell.2017.12.014

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

A quarter of all solid tumors harbor KRAS oncogenes. Yet, no selective drugs have been approved to treat these malignancies. Genetic interrogation of the MAPK pathway revealed that systemic ablation of MEK or ERK kinases in adult mice prevent tumor development but are unacceptably toxic. Here, we demonstrate that ablation of c-RAF expression in advanced tumors driven by Kras(G12V)/Trp53 mutations leads to significant tumor regression with no detectable appearance of resistance mechanisms. Tumor regression results from massive apoptosis. Importantly, systemic abrogation of c-RAF expression does not inhibit canonical MAPK signaling, hence, resulting in limited toxicities. These results are of significant relevance for the design of therapeutic strategies to treat K-RAS mutant cancers.

引用

页码：217 / +

页数：16

共 29 条

[1] c-Raf, but Not B-Raf, Is Essential for Development of K-Ras Oncogene-Driven Non-Small Cell Lung Carcinoma [J].