Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas

被引：16

作者：

Esteban-Burgos, Laura ^{[1
]}

Wang, Haiyun ^{[2
]}

Nieto, Patricia ^{[1
,10
]}

Zheng, Jie ^{[2
]}

Blanco-Aparicio, Carmen ^{[3
]}

Varela, Carmen ^{[4
]}

Gomez-Lopez, Gonzalo ^{[5
]}

Fernandez-Garcia, Fernando ^{[1
]}

Sanclemente, Manuel ^{[1
]}

Guerra, Carmen ^{[1
]}

Drosten, Matthias ^{[1
]}

Galan, Javier ^{[1
,11
]}

Caleiras, Eduardo ^{[6
]}

Martinez-Torrecuadrada, Jorge ^{[7
]}

Fajas, Lluis ^{[8
]}

Peng, Sheng-Bin ^{[9
]}

Santamaria, David ^{[1
,12
]}

Musteanu, Monica ^{[1
]}

Barbacid, Mariano ^{[1
]}

机构：

[1] Ctr Nacl Invest Oncol, Mol Oncol Programme, Expt Oncol, Madrid 28029, Spain

[2] Tongji Univ, Sch Life Sci & Technol, Shanghai 200092, Peoples R China

[3] Ctr Nacl Invest Oncol, Biol Sect, Expt Therapeut Programme, Madrid 28029, Spain

[4] Ctr Nacl Invest Oncol, Med Chem Sect, Expt Therapeut Programme, Madrid 28029, Spain

[5] Ctr Nacl Invest Oncol, Bioinformat Unit, Struct Biol Programme, Madrid 28029, Spain

[6] Ctr Nacl Invest Oncol, Histopathol Unit, Biotechnol Programme, Madrid 28029, Spain

[7] Ctr Nacl Invest Oncol, Crystallog & Prot Engn Unit, Struct Biol Programme, Madrid 28029, Spain

[8] Univ Lausanne, Ctr Integrat Genom, CH-1015 Lausanne, Switzerland

[9] Eli Lilly & Co, Oncol Res, Indianapolis, IN 46285 USA

[10] Asociac Espanola Canc, Madrid 28040, Spain

[11] Univ Francisco Vitoria, Fac Expt Sci, Madrid 28223, Spain

[12] Univ Bordeaux, Inst Europeen Chim & Biol, ACTION Lab, INSERM,U1218, F-33600 Pessac, France

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2020年 / 117卷 / 39期

基金：

欧洲研究理事会; 中国国家自然科学基金;

关键词：

KRAS; CDK4/RAF1; inhibition; Tumor Regression; Lung Cancer; Resistance Mechanisms; DEPENDENT KINASE-ACTIVITY; C-RAF; CANCER; MICE; INHIBITION; DOCETAXEL; EFFECTOR; STRATEGY; SURVIVAL; AFFINITY;

D O I：

10.1073/pnas.2002520117

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

KRAS mutant lung adenocarcinomas remain intractable for targeted therapies. Genetic interrogation of KRAS downstream effectors, including the MAPK pathway and the interphase CDKs, identified CDK4 and RAF1 as the only targets whose genetic inactivation induces therapeutic responses without causing unacceptable toxicities. Concomitant CDK4 inactivation and RAF1 ablation prevented tumor progression and induced complete regression in 25% of KRAS/p53-driven advanced lung tumors, yet a significant percentage of those tumors that underwent partial regression retained a population of CDK4/RAF1-resistant cells. Characterization of these cells revealed two independent resistance mechanisms implicating hypermethylation of several tumor suppressors and increased PI3K activity. Importantly, these CDK4/RAF1-resistant cells can be pharmacologically controlled. These studies open the door to new therapeutic strategies to treat KRAS mutant lung cancer, including resistant tumors.

引用

页码：24415 / 24426

页数：12

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