Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/14720
Título
Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas.
Autor(es)
Wang, Haiyun | Nieto, Patricia | Zheng, Jie | Gómez-López, Gonzalo CNIO | Fernández-García, Fernando | Sanclemente, Manuel CNIO | Drosten, Matthias CNIO | Galán, Javier | Fajas, Lluis | Peng, Sheng-Bin | Santamaria, David CNIO | Musteanu, Mónica CNIO | Esteban-Burgos, Laura CNIO | Blanco-Aparicio, Carmen CNIO | Varela, Carmen CNIO | Guerra, Carmen CNIO | Caleiras, E CNIO | Martinez Torrecuadrada, Jorge Luis CNIO | Barbacid, Mariano CNIO | Caleiras, Eduardo | Martínez-Torrecuadrada, Jorge
Fecha de publicación
2020-09-29
Cita
Proc Natl Acad Sci U S A . 2020 ;117(39):24415-24426.
Idioma
Inglés
Tipo de documento
journal article
Resumen
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.
MESH
Adenocarcinoma of Lung | Animals | Antineoplastic Agents | Cell Line, Tumor | Cyclin-Dependent Kinase 4 | Disease Progression | Drug Resistance, Neoplasm | Gene Silencing | Humans | Lung Neoplasms | Mice | Mice, Inbred C57BL | Mutation | Proto-Oncogene Proteins c-raf | Proto-Oncogene Proteins p21(ras) | Tumor Suppressor Protein p53
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