Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas
| Autor: | Wang, Haiyun, Nieto, Patricia, Zheng, Jie, Gómez-López, Gonzalo, Fernández-García, Fernando, Sanclemente, Manuel, Drosten, Matthias, Galán, Javier, Fajas, Lluis, Peng, Sheng-Bin, Santamaria, David, Musteanu, Mónica, Esteban-Burgos, Esteban-Burgos L, Blanco-Aparicio, Carmen, Varela, Carmen, Guerra, Carmen, Caleiras, E, Martinez Torrecuadrada, Jorge Luis, Barbacid, Mariano, Esteban-Burgos, Laura, Caleiras, Eduardo, Martínez-Torrecuadrada, Jorge |
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| Přispěvatelé: | European Research Council, European Commission, Ministerio de Economía, Industria y Competitividad (España), Comunidad de Madrid, National Natural Science Foundation of China, Fundación AXA |
| Rok vydání: | 2020 |
| Předmět: |
MAPK/ERK pathway
Lung Neoplasms endocrine system diseases Population Adenocarcinoma of Lung Antineoplastic Agents medicine.disease_cause Proto-Oncogene Proteins p21(ras) Mice Cyclin-dependent kinase Cell Line Tumor Medicine Animals Humans Gene Silencing Lung cancer education neoplasms PI3K/AKT/mTOR pathway education.field_of_study Multidisciplinary biology business.industry Cyclin-Dependent Kinase 4 Biological Sciences medicine.disease Mice Inbred C57BL Proto-Oncogene Proteins c-raf Tumor progression Drug Resistance Neoplasm DNA methylation Mutation Cancer research biology.protein Disease Progression KRAS Tumor Suppressor Protein p53 business |
| Zdroj: | Repisalud Instituto de Salud Carlos III (ISCIII) Proc Natl Acad Sci U S A |
| Popis: | 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. We thank S. Ortega for the generation of the Cdk4FxKD mouse model; and M. San Roman, R. Villar, M. C. Gonzalez, A. Lopez, N. Cabrera, P. Villanueva, J. Condo, J. Klett, A. Cebria, A. Otero, O. Dominguez, G. Luengo, G. Garaulet, F. Mulero, and D. Megias for excellent technical support. This work was supported by European Research Council Grant ERC-2015-AdG/695566, THERACAN, Spanish Ministry of Science, Innovation, and Universities Grant RTC-2017-6576-1, and the Autonomous Community of Madrid Grant B2017/BMD-3884 iLUNG-CM (to M.B.); Spanish Ministry of Science, Innovation, and Universities Grant RTI2018-094664B-I00 (to M.B. and M.M.); and National Natural Science Foundation of China Grant 31771469 (to H.W.). M.B. is a recipient of an Endowed Chair from the AXA Research Fund. L.E.-B. is the recipient of an FPI fellowship from the Spanish Ministry of Economy and Competitiveness. F.F.-G., M.S., and P.N. were supported by an FPU fellowships from the Spanish Ministry of Education. Sí |
| Databáze: | OpenAIRE |
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