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

Bosch-Barrera, Joaquim; Verdura, Sara; Ruffinelli, J.C.; Carcereny, Enric; Sais, Elia; Cuyàs, Elisabet; Palmero, Ramón; López-Bonet, Eugeni; Hernández-Martínez, Alejandro; Oliveras, Glòria; Buxó, María; Izquierdo, Àngel; Morán, Teresa; Nadal, Ernest; Menéndez, Javier A.

doi:10.3390/cancers13164168

Cited by 9 publications

(3 citation statements)

References 83 publications

(124 reference statements)

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“…Some studies have reported that STAT3 pathway activation may contribute to increase PD-L1, TAP1 and MHC-I levels [39,62,63]. In addition, based on extensive research, the effect of nintedanib on the STAT3 pathway mainly depends on the concentration and cell responsiveness [64][65][66]. Herein, our in vitro results demonstrated that a low concentration of nintedanib (1 μM) can promote STAT3 phosphorylation and downstream protein expression (PD-L1 and β2M) in different tumor cell lines (A549, MC38 and LLC) and gradually suppress these pathways at high doses (5 μM).…”

Section: Discussionmentioning

confidence: 99%

Nintedanib enhances the efficacy of PD-L1 blockade by upregulating MHC-I and PD-L1 expression in tumor cells

Tu¹,

Xu²,

Ma³

et al. 2022

Theranostics

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Background: Immune checkpoint inhibitors (ICIs), such as programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), have been widely applied in clinical and scientific research. Despite their effective antitumor effects in clinical tumor therapy, most tumors are still resistant to ICIs and long-term benefits are lacking. In addition, tumor patients complicated with interstitial lung disease limit the application of ICI therapy. Therefore, for these cases, there is an urgent need to develop new methods to relieve lung complications and enhance the efficacy of ICI therapy. Nintedanib, a potent triple angiokinase inhibitor approved for the treatment of progressive fibrotic interstitial lung disease. However, its immunotherapy synergy properties and mechanism are still pending further exploration. Methods:To explore the therapeutic potential of nintedanib and αPD-L1 combination therapy, MC38, LLC, and 4T1 tumor models were used to investigate antitumor and antimetastatic activities in vivo. An idiopathic pulmonary fibrosis-tumor bearing model was used to evaluate the effect of the synergy therapy on tumor model complicated with lung disease. Moreover, RNA-seq, immunohistochemistry, and flow cytometry were utilized to analyze the effect of combination treatment on the tumor microenvironment. The bioactivity following different treatments was determined by western blotting, CCK-8, and flow cytometry.Results: In this study, nintedanib and αPD-L1 synergy therapy exhibited significant antitumor, antimetastatic and anti-pulmonary fibrosis effects. Both in vitro and in vivo experiments revealed that these effects included promoting vessel normalization, increasing infiltration and activation of immune cells in tumors, enhancing the response of interferon-gamma, and activating the MHC class I-mediated antigen presentation process. Moreover, our results showed an increased expression of PD-L1 and promoted phosphorylation of STAT3 after nintedanib (1 µM) treatment. Conclusion:The combination of nintedanib and αPD-L1 increased ICI therapy responses, relieved lung complications and further activated the tumor immune microenvironment; thus, exhibiting a notable antitumor effect. Accordingly, the nintedanib synergy strategy is expected to be a promising candidate therapy for tumor patients complicated with interstitial lung disease in clinical practice.

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Section: Discussionmentioning

confidence: 99%

Nintedanib enhances the efficacy of PD-L1 blockade by upregulating MHC-I and PD-L1 expression in tumor cells

Tu¹,

Xu²,

Ma³

et al. 2022

Theranostics

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“…In recent years, nintedanib has been suggested to have anti-tumor effects (25,(45)(46)(47)(48) .Researchers now believe that nintedanib's antitumor effect is associated with its ability to inhibit tumor growth in a CD8 + T cell-dependent manner while also inhibiting broblast proliferation and activation (48) .…”

Section: Discussionmentioning

confidence: 99%

Expression profiles of nintedanib-targeting molecules in progressive fibrotic interstitial lung diseases (non-IPF-PF) and IPF

Zhang

Wang

et al. 2023

Preprint

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Background: Idiopathic pulmonary fibrosis (IPF) and other types of progressive fibrotic interstitial lung diseases (non-IPF-PF), such as chronic hypersensitivity pneumonitis (cHP), systemic sclerosis (SSc), non-specific interstitial pneumonia (NSIP), and sarcoidosis, are common interstitial lung diseases. Nintedanib is one of the two approved therapies that can significantly slow the progression of IPF. However, the potential of nintedanib in non-IPF-PF has not been fully evaluated. Methods: We reanalyzed the single-cell data of IPF and non-IPF-PF and identified the main target genes of nintedanib (FGFR1, FGFR2, FGFR3, FLT1, FLT4, KDR, and PDGFRA) by subgroup classification and functional analysis of gene expression profiles in both IPF and non-IPF-PF. Results: We found that the main target genes of nintedanib were upregulated in IPF and various cell subpopulations of non-IPF-PF, including cHP, SSc, NSIP, and sarcoidosis, with Fgfr1 being the most elevated subpopulation. In fibroblasts, Fgfr1 was found to be elevated in both IPF and cHP. We identified nintedanib-sensitive cell subpopulations by analyzing the expression profiles of fibroblasts after nintedanib treatment. We also found that nintedanib could inhibit the nintedanib-sensitive gene set in mice treated with nintedanib in vivo. Furthermore, we demonstrated that key regulatory genes of nintedanib were positively correlated with survival in lung adenocarcinoma, providing further support for the potential anti-tumor activity of nintedanib in vivo. Conclusion: Our findings provide comprehensive evidence of the target expression of nintedanib in non-IPF-PF and IPF, highlighting the potential of nintedanib for the treatment of non-IPF-PF.

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“…EMT-driven NSCLC cross-resistance can be abrogated by silibinin, which directly inhibits TGFβR kinase activity and blocks the SMAD signaling cascade in mesenchymal ALK-rearranged NSCLC cells. As EMT is an increasingly recognized driver of innate and acquired resistance to various cytotoxic and targeted drugs, clinically-relevant bioavailable formulations of silibinin with proven anti-cancer activity [ 103 , 104 , 105 ] could be explored as cost-effective and feasible approaches for patients with NSCLC resistant to ALK–TKIs.…”

Section: Discussionmentioning

confidence: 99%

Silibinin Overcomes EMT-Driven Lung Cancer Resistance to New-Generation ALK Inhibitors

Verdura

Encinar

Teixidor

et al. 2022

Cancers

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Epithelial-to-mesenchymal transition (EMT) may drive the escape of ALK-rearranged non-small-cell lung cancer (NSCLC) tumors from ALK-tyrosine kinase inhibitors (TKIs). We investigated whether first-generation ALK–TKI therapy-induced EMT promotes cross-resistance to new-generation ALK–TKIs and whether this could be circumvented by the flavonolignan silibinin, an EMT inhibitor. ALK-rearranged NSCLC cells acquiring a bona fide EMT phenotype upon chronic exposure to the first-generation ALK–TKI crizotinib exhibited increased resistance to second-generation brigatinib and were fully refractory to third-generation lorlatinib. Such cross-resistance to new-generation ALK–TKIs, which was partially recapitulated upon chronic TGFβ stimulation, was less pronounced in ALK-rearranged NSCLC cells solely acquiring a partial/hybrid E/M transition state. Silibinin overcame EMT-induced resistance to brigatinib and lorlatinib and restored their efficacy involving the transforming growth factor-beta (TGFβ)/SMAD signaling pathway. Silibinin deactivated TGFβ-regulated SMAD2/3 phosphorylation and suppressed the transcriptional activation of genes under the control of SMAD binding elements. Computational modeling studies and kinase binding assays predicted a targeted inhibitory binding of silibinin to the ATP-binding pocket of TGFβ type-1 receptor 1 (TGFBR1) and TGFBR2 but solely at the two-digit micromolar range. A secretome profiling confirmed the ability of silibinin to normalize the augmented release of TGFβ into the extracellular fluid of ALK–TKIs-resistant NSCLC cells and reduce constitutive and inducible SMAD2/3 phosphorylation occurring in the presence of ALK–TKIs. In summary, the ab initio plasticity along the EMT spectrum may explain the propensity of ALK-rearranged NSCLC cells to acquire resistance to new-generation ALK–TKIs, a phenomenon that could be abrogated by the silibinin-driven attenuation of the TGFβ/SMAD signaling axis in mesenchymal ALK-rearranged NSCLC cells.

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

Cited by 9 publications

References 83 publications

Nintedanib enhances the efficacy of PD-L1 blockade by upregulating MHC-I and PD-L1 expression in tumor cells

Nintedanib enhances the efficacy of PD-L1 blockade by upregulating MHC-I and PD-L1 expression in tumor cells

Expression profiles of nintedanib-targeting molecules in progressive fibrotic interstitial lung diseases (non-IPF-PF) and IPF

Silibinin Overcomes EMT-Driven Lung Cancer Resistance to New-Generation ALK Inhibitors

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