Silibinin Suppresses Tumor Cell-Intrinsic Resistance to Nintedanib and Enhances Its Clinical Activity in Lung Cancer

Autor: Elisabet Cuyàs, Jose Carlos Ruffinelli, Eugeni López-Bonet, Alejandro Hernández-Martínez, Elia Sais, Maria Buxó, Teresa Moran, Javier A. Menendez, Angel Izquierdo, Enric Carcereny, Joaquim Bosch-Barrera, Ramon Palmero, Glòria Oliveras, Ernest Nadal, Sara Verdura
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Cancers, Vol 13, Iss 4168, p 4168 (2021)
Cancers
Cancers; Volume 13; Issue 16; Pages: 4168
r-IGTP. Repositorio Institucional de Producción Científica del Instituto de Investigación Germans Trias i Pujol
instname
Dipòsit Digital de la UB
Universidad de Barcelona
Cancers, 2021, vol. 13, núm. 16, p. 4168
Articles publicats (IdIBGi)
Bosch Barrera, Joaquim Verdura, Sara Ruffinelli, José Carlos Carcereny, Enric Sais, Elia Cuyàs, Elisabet Palmero, Ramon López Bonet, Eugeni Hernández-Martínez, Alejandro Oliveras, Glòria Buxó Pujolràs, Maria Izquierdo i Font, Àngel Xavier Morán, Teresa Nadal, Ernest Menéndez Menéndez, Javier Abel 2021 Silibinin suppresses tumor cell-intrinsic resistance to Nintedanib and enhances its clinical cctivity in Lung Cancer Cancers 13 16 4168
DUGiDocs – Universitat de Girona
ISSN: 2072-6694
Popis: Simple Summary Nintedanib is an anti-angiogenic agent that has received approval in the European Union for the treatment of non-small cell lung cancer (NSCLC) after first-line chemotherapy. Here, we explore the possibility that the flavonolignan silibinin—the major bioactive component from the seeds of the milk thistle herb (Silybum marianum)—can provide clinical benefit in patients with advanced NSCLC treated with nintedanib. In vitro studies revealed that silibinin targets biological functions important for the therapeutic efficacy of nintedanib; specifically, activation of the transcription factor STAT3 and sequestration into lysosomal “safe houses”. Supplementation with the silibinin-based nutraceutical Legasil® to patients with NSCLC receiving nintedanib/docetaxel was associated with increased clinical responses and a significantly longer time to treatment failure. Our findings provide a biological and clinical rationale for combining silibinin with nintedanib in a patient population for whom few effective second-line chemotherapy regimens are available. 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.
Databáze: OpenAIRE
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