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http://hdl.handle.net/2445/179941
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DC Field | Value | Language |
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dc.contributor.author | Bosch Barrera, Joaquim | - |
dc.contributor.author | Verdura, Sara | - |
dc.contributor.author | Ruffinelli, José Carlos | - |
dc.contributor.author | Carcereny, Enric | - |
dc.contributor.author | Sais, Elia | - |
dc.contributor.author | Cuyàs, Elisabet | - |
dc.contributor.author | Palmero, Ramón | - |
dc.contributor.author | Lopez Bonet, Eugeni | - |
dc.contributor.author | Hernández Martínez, Alejandro | - |
dc.contributor.author | Oliveras Serrat, Glòria | - |
dc.contributor.author | Buxó, Maria | - |
dc.contributor.author | Izquierdo, Angel | - |
dc.contributor.author | Morán, Teresa | - |
dc.contributor.author | Nadal, Ernest | - |
dc.contributor.author | Menendez, Javier A. | - |
dc.date.accessioned | 2021-09-13T06:51:48Z | - |
dc.date.available | 2021-09-13T06:51:48Z | - |
dc.date.issued | 2021-08-19 | - |
dc.identifier.issn | 2072-6694 | - |
dc.identifier.uri | http://hdl.handle.net/2445/179941 | - |
dc.description.abstract | The anti-angiogenic agent nintedanib has been shown to prolong overall and progression-free survival in patients with advanced non-small-cell lung cancer (NSCLC) who progress after first-line platinum-based chemotherapy and second-line immunotherapy. Here, we explored the molecular basis and the clinical benefit of incorporating the STAT3 inhibitor silibinin-a flavonolignan extracted from milk thistle-into nintedanib-based schedules in advanced NSCLC. First, we assessed the nature of the tumoricidal interaction between nintedanib and silibinin and the underlying relevance of STAT3 activation in a panel of human NSCLC cell lines. NSCLC cells with poorer cytotoxic responses to nintedanib exhibited a persistent, nintedanib-unresponsive activated STAT3 state, and deactivation by co-treatment with silibinin promoted synergistic cytotoxicity. Second, we tested whether silibinin could impact the lysosomal sequestration of nintedanib, a lung cancer cell-intrinsic mechanism of nintedanib resistance. Silibinin partially, but significantly, reduced the massive lysosomal entrapment of nintedanib occurring in nintedanib-refractory NSCLC cells, augmenting the ability of nintedanib to reach its intracellular targets. Third, we conducted a retrospective, observational multicenter study to determine the efficacy of incorporating an oral nutraceutical product containing silibinin in patients with NSCLC receiving a nintedanib/docetaxel combination in second- and further-line settings (n = 59). Overall response rate, defined as the combined rates of complete and partial responses, was significantly higher in the study cohort receiving silibinin supplementation (55%) than in the control cohort (22%, p = 0.011). Silibinin therapy was associated with a significantly longer time to treatment failure in multivariate analysis (hazard ratio 0.43, p = 0.013), despite the lack of overall survival benefit (hazard ratio 0.63, p = 0.190). Molecular mechanisms dictating the cancer cell-intrinsic responsiveness to nintedanib, such as STAT3 activation and lysosomal trapping, are amenable to pharmacological intervention with silibinin. A prospective, powered clinical trial is warranted to confirm the clinical relevance of these findings in patients with advanced NSCLC. | - |
dc.format.extent | 27 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | MDPI AG | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.3390/cancers13164168 | - |
dc.relation.ispartof | Cancers, 2021, vol. 13, num. 16, p. 4168 | - |
dc.relation.uri | https://doi.org/10.3390/cancers13164168 | - |
dc.rights | cc by (c) Bosch Barrera, Joaquim et al, 2021 | - |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.source | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) | - |
dc.subject.classification | Càncer de pulmó | - |
dc.subject.classification | Terapèutica | - |
dc.subject.other | Lung cancer | - |
dc.subject.other | Therapeutics | - |
dc.title | Silibinin Suppresses Tumor Cell-Intrinsic Resistance to Nintedanib and Enhances Its Clinical Activity in Lung Cancer | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.date.updated | 2021-09-10T11:17:49Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 34439322 | - |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
Files in This Item:
File | Description | Size | Format | |
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cancers-13-04168.pdf | 5.62 MB | Adobe PDF | View/Open |
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