Bosch Barrera, JoaquimVerdura, SaraRuffinelli, José CarlosCarcereny, EnricSais, EliaCuyàs, ElisabetPalmero, RamónLópez Bonet, EugeniHernández Martínez, AlejandroOliveras Serrat, GlòriaBuxó, MariaIzquierdo, AngelMorán, TeresaNadal, ErnestMenendez, Javier A.2021-09-132021-09-132021-08-192072-6694https://hdl.handle.net/2445/179941The 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.27 p.application/pdfengcc by (c) Bosch Barrera, Joaquim et al, 2021http://creativecommons.org/licenses/by/3.0/es/Càncer de pulmóTerapèuticaLung cancerTherapeuticsinfo:eu-repo/semantics/article2021-09-10info:eu-repo/semantics/openAccess34439322