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dc.contributor.authorBosch Barrera, Joaquim-
dc.contributor.authorVerdura, Sara-
dc.contributor.authorRuffinelli, José Carlos-
dc.contributor.authorCarcereny, Enric-
dc.contributor.authorSais, Elia-
dc.contributor.authorCuyàs, Elisabet-
dc.contributor.authorPalmero, Ramón-
dc.contributor.authorLopez Bonet, Eugeni-
dc.contributor.authorHernández Martínez, Alejandro-
dc.contributor.authorOliveras Serrat, Glòria-
dc.contributor.authorBuxó, Maria-
dc.contributor.authorIzquierdo, Angel-
dc.contributor.authorMorán, Teresa-
dc.contributor.authorNadal, Ernest-
dc.contributor.authorMenendez, Javier A.-
dc.description.abstractThe 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.extent27 p.-
dc.publisherMDPI AG-
dc.relation.isformatofReproducció del document publicat a:
dc.relation.ispartofCancers, 2021, vol. 13, num. 16, p. 4168-
dc.rightscc by (c) Bosch Barrera, Joaquim et al, 2021-
dc.subject.classificationCàncer de pulmó-
dc.subject.otherLung cancer-
dc.titleSilibinin Suppresses Tumor Cell-Intrinsic Resistance to Nintedanib and Enhances Its Clinical Activity in Lung Cancer-
Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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