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

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dc.contributor.authorWang, Haiyun
dc.contributor.authorNieto, Patricia
dc.contributor.authorZheng, Jie
dc.contributor.authorGómez-López, Gonzalo
dc.contributor.authorFernández-García, Fernando
dc.contributor.authorSanclemente, Manuel
dc.contributor.authorDrosten, Matthias
dc.contributor.authorGalán, Javier
dc.contributor.authorFajas, Lluis
dc.contributor.authorPeng, Sheng-Bin
dc.contributor.authorSantamaria, David
dc.contributor.authorMusteanu, Mónica
dc.contributor.authorEsteban-Burgos, Laura
dc.contributor.authorBlanco-Aparicio, Carmen
dc.contributor.authorVarela Bustos, Carmen
dc.contributor.authorGuerra, Carmen
dc.contributor.authorCaleiras, E
dc.contributor.authorMartinez Torrecuadrada, Jorge Luis
dc.contributor.authorBarbacid, Mariano
dc.contributor.authorCaleiras, Eduardo
dc.contributor.authorMartínez-Torrecuadrada, Jorge
dc.contributor.funderUnión Europea. Comisión Europea. European Research Council (ERC)
dc.contributor.funderUnión Europea. Comisión Europea
dc.contributor.funderMinisterio de Economía, Industria y Competitividad (España)
dc.contributor.funderComunidad de Madrid (España)
dc.contributor.funderNational Natural Science Foundation of China
dc.contributor.funderFundación AXA
dc.date.accessioned2022-07-14T11:41:46Z
dc.date.available2022-07-14T11:41:46Z
dc.date.issued2020-09-29
dc.description.abstractKRAS 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.es_ES
dc.description.peerreviewedSíes_ES
dc.description.sponsorshipWe 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.es_ES
dc.format.number39es_ES
dc.format.page24415-24426es_ES
dc.format.volume117es_ES
dc.identifier.citationProc Natl Acad Sci U S A . 2020 ;117(39):24415-24426.es_ES
dc.identifier.doi10.1073/pnas.2002520117es_ES
dc.identifier.e-issn1091-6490es_ES
dc.identifier.issn0027-8424es_ES
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of Americaes_ES
dc.identifier.pubmedID32913049es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/14720
dc.language.isoenges_ES
dc.publisherNational Academy of Sciences
dc.relation.projectFISinfo:eu-repo/grantAgreement/ES/RTI2018-094664B-I00es_ES
dc.relation.projectFISinfo:eu-repo/grantAgreement/ES/RTC-2017-6576-1es_ES
dc.relation.projectFISinfo:eu-repo/grantAgreement/ES/B2017/BMD-3884 iLUNG-CMes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/H2020/695566/EUes_ES
dc.relation.publisherversionhttps://doi.org/10.1073/pnas.2002520117es_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigación::Grupo de Oncología Experimentales_ES
dc.rights.accessRightsopen accesses_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAdenocarcinoma of Lunges_ES
dc.subject.meshAnimalses_ES
dc.subject.meshAntineoplastic Agentses_ES
dc.subject.meshCell Line, Tumores_ES
dc.subject.meshCyclin-Dependent Kinase 4es_ES
dc.subject.meshDisease Progressiones_ES
dc.subject.meshDrug Resistance, Neoplasmes_ES
dc.subject.meshGene Silencinges_ES
dc.subject.meshHumanses_ES
dc.subject.meshLung Neoplasmses_ES
dc.subject.meshMicees_ES
dc.subject.meshMice, Inbred C57BLes_ES
dc.subject.meshMutationes_ES
dc.subject.meshProto-Oncogene Proteins c-rafes_ES
dc.subject.meshProto-Oncogene Proteins p21(ras)es_ES
dc.subject.meshTumor Suppressor Protein p53es_ES
dc.titleTumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas.es_ES
dc.typejournal articlees_ES
dc.type.hasVersionVoRes_ES
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