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dc.contributor.author | Trigg, Ricky M | |
dc.contributor.author | Lee, Liam C | |
dc.contributor.author | Prokoph, Nina | |
dc.contributor.author | Jahangiri, Leila | |
dc.contributor.author | Reynolds, C Patrick | |
dc.contributor.author | Amos Burke, G A | |
dc.contributor.author | Probst, Nicola A | |
dc.contributor.author | Han, Miaojun | |
dc.contributor.author | Matthews, Jamie D | |
dc.contributor.author | Lim, Hong Kai | |
dc.contributor.author | Manners, Eleanor | |
dc.contributor.author | Martinez, Sonia | |
dc.contributor.author | Pastor Fernandez, Joaquin | |
dc.contributor.author | Blanco-Aparicio, Carmen | |
dc.contributor.author | Merkel, Olaf | |
dc.contributor.author | Garces de Los Fayos Alonso, Ines | |
dc.contributor.author | Kodajova, Petra | |
dc.contributor.author | Tangermann, Simone | |
dc.contributor.author | Högler, Sandra | |
dc.contributor.author | Luo, Ji | |
dc.contributor.author | Kenner, Lukas | |
dc.contributor.author | Turner, Suzanne D | |
dc.date.accessioned | 2020-03-20T19:34:33Z | |
dc.date.available | 2020-03-20T19:34:33Z | |
dc.date.issued | 2019-11-28 | |
dc.identifier.citation | Nat Commun. 2019 Nov 28;10(1):5428. | es_ES |
dc.identifier.issn | 2041-1723 | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/9298 | |
dc.description.abstract | Resistance 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.sponsorship | This 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 Foundation | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Nature Publishing Group | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | * |
dc.subject.mesh | Anaplastic Lymphoma Kinase | es_ES |
dc.subject.mesh | Animals | es_ES |
dc.subject.mesh | Apoptosis | es_ES |
dc.subject.mesh | Biphenyl Compounds | es_ES |
dc.subject.mesh | Cell Line, Tumor | es_ES |
dc.subject.mesh | Drug Resistance, Neoplasm | es_ES |
dc.subject.mesh | Gene Knockdown Techniques | es_ES |
dc.subject.mesh | Humans | es_ES |
dc.subject.mesh | Mice | es_ES |
dc.subject.mesh | N-Myc Proto-Oncogene Protein | es_ES |
dc.subject.mesh | Neuroblastoma | es_ES |
dc.subject.mesh | Organophosphorus Compounds | es_ES |
dc.subject.mesh | Protein Kinase Inhibitors | es_ES |
dc.subject.mesh | Proto-Oncogene Proteins c-pim-1 | es_ES |
dc.subject.mesh | Pyrimidines | es_ES |
dc.subject.mesh | Sulfones | es_ES |
dc.subject.mesh | Thiazolidines | es_ES |
dc.subject.mesh | Xenograft Model Antitumor Assays | es_ES |
dc.title | The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución-NoComercial-CompartirIgual 4.0 Internacional | * |
dc.identifier.pubmedID | 31780656 | es_ES |
dc.format.volume | 10 | es_ES |
dc.format.number | 1 | es_ES |
dc.format.page | 5428 | es_ES |
dc.identifier.doi | 10.1038/s41467-019-13315-x | es_ES |
dc.contributor.funder | Children with Cancer UK | |
dc.contributor.funder | Cancer Research UK (Reino Unido) | |
dc.contributor.funder | Unión Europea. Comisión Europea. European Research Council (ERC) | |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 2041-1723 | es_ES |
dc.relation.publisherversion | https://doi.org/10.1038/s41467-019-13315-x. | es_ES |
dc.identifier.journal | Nature communications | es_ES |
dc.repisalud.institucion | CNIO | es_ES |
dc.repisalud.orgCNIO | CNIO::Grupos de investigación::Sección de Química Médica | es_ES |
dc.relation.projectID | info:eu_repo/grantAgreement/EC/H2020/675712 | es_ES |
dc.rights.accessRights | open access | es_ES |