2026-05-17T00:18:16Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/147202024-11-29T19:17:30Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc 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 author 2020-09-29 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. 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 Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas.