2026-05-17T00:18:17Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/147202024-11-29T19:17:30Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Wang, Haiyun
author
Nieto, Patricia
author
Zheng, Jie
author
Gómez-López, Gonzalo
author
Fernández-García, Fernando
author
Sanclemente, Manuel
author
Drosten, Matthias
author
Galán, Javier
author
Fajas, Lluis
author
Peng, Sheng-Bin
author
Santamaria, David
author
Musteanu, Mónica
author
Esteban-Burgos, Laura
author
Blanco-Aparicio, Carmen
author
Varela Bustos, Carmen
author
Guerra, Carmen
author
Caleiras, E
author
Martinez Torrecuadrada, Jorge Luis
author
Barbacid, Mariano
author
Caleiras, Eduardo
author
Martínez-Torrecuadrada, Jorge
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
funder
Unión Europea. Comisión Europea
funder
Ministerio de Economía, Industria y Competitividad (España)
funder
Comunidad de Madrid (España)
funder
National Natural Science Foundation of China
funder
Fundación AXA
2022-07-14T11:41:46Z
2022-07-14T11:41:46Z
2020-09-29
Proc Natl Acad Sci U S A . 2020 ;117(39):24415-24426.
10.1073/pnas.2002520117
1091-6490
0027-8424
Proceedings of the National Academy of Sciences of the United States of America
32913049
http://hdl.handle.net/20.500.12105/14720
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.
eng
Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas.
journal article
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