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dc.contributor.authorEritja Sánchez, Núria
dc.contributor.authorChen, Bo-Juen
dc.contributor.authorRodríguez Barrueco, Ruth
dc.contributor.authorSantacana Espasa, Maria
dc.contributor.authorGatius Calderó, Sònia
dc.contributor.authorVidal, August
dc.contributor.authorMartí, Maria Dolores
dc.contributor.authorPonce, Jordi
dc.contributor.authorBergadà Bertran, Laura
dc.contributor.authorYeramian Hakim, Andree
dc.contributor.authorEncinas Martín, Mario
dc.contributor.authorRibera i Calvet, Joan
dc.contributor.authorReventós, Jaume
dc.contributor.authorBoyd, Jeff
dc.contributor.authorVillanueva, Alberto
dc.contributor.authorMatias-Guiu, Xavier
dc.contributor.authorDolcet Roca, Xavier
dc.contributor.authorLlobet Navàs, David
dc.date.accessioned2017-02-21T11:19:30Z
dc.date.available2017-02-21T11:19:30Z
dc.date.issued2017
dc.identifier.issn1554-8627
dc.identifier.urihttp://hdl.handle.net/10459.1/59294
dc.description.abstractTargeted therapies in endometrial cancer (EC) using kinase inhibitors rarely result in complete tumor remission and are frequently challenged by the appearance of refractory cell clones, eventually resulting in disease relapse. Dissecting adaptive mechanisms is of vital importance to circumvent clinical drug resistance and improve the efficacy of targeted agents in EC. Sorafenib is an FDA-approved multitarget tyrosine and serine/threonine kinase inhibitor currently used to treat hepatocellular carcinoma, advanced renal carcinoma and radioactive iodine-resistant thyroid carcinoma. Unfortunately, sorafenib showed very modest effects in a multi-institutional phase II trial in advanced uterine carcinoma patients. Here, by leveraging RNA-sequencing data from the Cancer Cell Line Encyclopedia and cell survival studies from compound-based high-throughput screenings we have identified the lysosomal pathway as a potential compartment involved in the resistance to sorafenib. By performing additional functional biology studies we have demonstrated that this resistance could be related to macroautophagy/autophagy. Specifically, our results indicate that sorafenib triggers a mechanistic MAPK/JNK-dependent early protective autophagic response in EC cells, providing an adaptive response to therapeutic stress. By generating in vivo subcutaneous EC cell line tumors, lung metastatic assays and primary EC orthoxenografts experiments, we demonstrate that targeting autophagy enhances sorafenib cytotoxicity and suppresses tumor growth and pulmonary metastasis progression. In conclusion, sorafenib induces the activation of a protective autophagic response in EC cells. These results provide insights into the unopposed resistance of advanced EC to sorafenib and highlight a new strategy for therapeutic intervention in recurrent EC.ca_ES
dc.description.sponsorshipThis work was supported by MINECO (SAF2016-80157-R), the Fondo de Investigaciones Sanitarias (PI10/00922, PI10/00604, PI13/01339 and PIE13–00022 (Oncoprofile)), Grant 2009SGR794 (Barcelona, Spain), Fundaci on Asociaci on Espa~nola Contra el C ancer (AECC-2011), AECC_- Barcelona and RETICS (RD12/0036/0013). DLN is recipient of a NURF scheme. The funders had no involvement in the study design, execution, analysis or interpretation of data and writing of the manuscript.ca_ES
dc.language.isoengca_ES
dc.publisherTaylor & Francisca_ES
dc.relation.isformatofReproducció del document publicat a https://doi.org/10.1080/15548627.2016.1271512ca_ES
dc.relation.ispartofAutophagy, 2017, vol. 13, núm. 3, p. 1-17ca_ES
dc.rightscc-by (c) Núria Eritja, et al. 2017ca_ES
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/es/*
dc.subjectAutophagyca_ES
dc.subjectEndometrial cancerca_ES
dc.subjectKinaseca_ES
dc.subjectLysosomesca_ES
dc.subjectMAPK/JNKca_ES
dc.subjectPDXca_ES
dc.subjectSorafenibca_ES
dc.subjectTargeted therapyca_ES
dc.titleAutophagy orchestrates adaptive responses to targeted therapy in endometrial cancerca_ES
dc.typearticleca_ES
dc.identifier.idgrec025482
dc.type.versionpublishedVersionca_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccessca_ES
dc.identifier.doihttps://doi.org/10.1080/15548627.2016.1271512


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cc-by (c) Núria Eritja, et al. 2017
Except where otherwise noted, this item's license is described as cc-by (c) Núria Eritja, et al. 2017