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dc.contributor.authorTrigg, Ricky M
dc.contributor.authorLee, Liam C
dc.contributor.authorProkoph, Nina
dc.contributor.authorJahangiri, Leila
dc.contributor.authorReynolds, C Patrick
dc.contributor.authorAmos Burke, G A
dc.contributor.authorProbst, Nicola A
dc.contributor.authorHan, Miaojun
dc.contributor.authorMatthews, Jamie D
dc.contributor.authorLim, Hong Kai
dc.contributor.authorManners, Eleanor
dc.contributor.authorMartinez, Sonia
dc.contributor.authorPastor Fernandez, Joaquin 
dc.contributor.authorBlanco-Aparicio, Carmen 
dc.contributor.authorMerkel, Olaf
dc.contributor.authorGarces de Los Fayos Alonso, Ines
dc.contributor.authorKodajova, Petra
dc.contributor.authorTangermann, Simone
dc.contributor.authorHögler, Sandra
dc.contributor.authorLuo, Ji
dc.contributor.authorKenner, Lukas
dc.contributor.authorTurner, Suzanne D
dc.date.accessioned2020-03-20T19:34:33Z
dc.date.available2020-03-20T19:34:33Z
dc.date.issued2019-11-28
dc.identifier.citationNat Commun. 2019 Nov 28;10(1):5428.es_ES
dc.identifier.issn2041-1723es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/9298
dc.description.abstractResistance to anaplastic lymphoma kinase (ALK)-targeted therapy in ALK-positive non-small cell lung cancer has been reported, with the majority of acquired resistance mechanisms relying on bypass signaling. To proactively identify resistance mechanisms in ALK-positive neuroblastoma (NB), we herein employ genome-wide CRISPR activation screens of NB cell lines treated with brigatinib or ceritinib, identifying PIM1 as a putative resistance gene, whose high expression is associated with high-risk disease and poor survival. Knockdown of PIM1 sensitizes cells of differing MYCN status to ALK inhibitors, and in patient-derived xenografts of high-risk NB harboring ALK mutations, the combination of the ALK inhibitor ceritinib and PIM1 inhibitor AZD1208 shows significantly enhanced anti-tumor efficacy relative to single agents. These data confirm that PIM1 overexpression decreases sensitivity to ALK inhibitors in NB, and suggests that combined front-line inhibition of ALK and PIM1 is a viable strategy for the treatment of ALK-positive NB independent of MYCN status.es_ES
dc.description.sponsorshipThis research is supported with funding from Children with Cancer UK (CWCUK; 16-209) awarded to S.D.T. and L.C.L., R.M.T. was supported by the CWCUK grant and L.C.L. was in receipt of a Cancer Research UK Cambridge Centre Paediatric Programme PhD studentship. N.P., L.J., O.M., I.G.F.A., L.K. and S.D.T. are supported by a European Union Horizon 2020 Marie Skłodowska–Curie Innovative Training Networks (ITN-ETN) Grant, Grant No.: 675712. N.A.P. was supported by ERASMUS+. We are grateful to AstraZeneca for providing us with AZD1208 and Inflection Biosciences for providing us with PIMi. We thank Isaia Barbieri for critical suggestions on the manuscript, BBSCR NIHR Cell phenotyping hub for flow cytometry expertise, the Bauer Core Facility at Harvard University for sequencing, and Liew Jun Mun and Stephen P. Ducray for technical assistance. Funding for the COG/ALSF Childhood Cancer Repository was provided by Alex’s Lemonade Stand Foundationes_ES
dc.language.isoenges_ES
dc.publisherNature Publishing Group es_ES
dc.type.hasVersionVoRes_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAnaplastic Lymphoma Kinase es_ES
dc.subject.meshAnimals es_ES
dc.subject.meshApoptosis es_ES
dc.subject.meshBiphenyl Compounds es_ES
dc.subject.meshCell Line, Tumor es_ES
dc.subject.meshDrug Resistance, Neoplasm es_ES
dc.subject.meshGene Knockdown Techniques es_ES
dc.subject.meshHumans es_ES
dc.subject.meshMice es_ES
dc.subject.meshN-Myc Proto-Oncogene Protein es_ES
dc.subject.meshNeuroblastoma es_ES
dc.subject.meshOrganophosphorus Compounds es_ES
dc.subject.meshProtein Kinase Inhibitors es_ES
dc.subject.meshProto-Oncogene Proteins c-pim-1 es_ES
dc.subject.meshPyrimidines es_ES
dc.subject.meshSulfones es_ES
dc.subject.meshThiazolidines es_ES
dc.subject.meshXenograft Model Antitumor Assays es_ES
dc.titleThe targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN statuses_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.identifier.pubmedID31780656es_ES
dc.format.volume10es_ES
dc.format.number1es_ES
dc.format.page5428es_ES
dc.identifier.doi10.1038/s41467-019-13315-xes_ES
dc.contributor.funderChildren with Cancer UK 
dc.contributor.funderCancer Research UK (Reino Unido) 
dc.contributor.funderUnión Europea. Comisión Europea. European Research Council (ERC) 
dc.description.peerreviewedes_ES
dc.identifier.e-issn2041-1723es_ES
dc.relation.publisherversionhttps://doi.org/10.1038/s41467-019-13315-x.es_ES
dc.identifier.journalNature communicationses_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigación::Sección de Química Médicaes_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/EC/H2020/675712es_ES
dc.rights.accessRightsopen accesses_ES


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