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Silibinin Overcomes EMT-Driven Lung Cancer Resistance to New-Generation ALK Inhibitors
dc.contributor.author | Verdura, Sara | |
dc.contributor.author | Segura Carretero, Antonio | |
dc.date.accessioned | 2023-01-26T13:35:23Z | |
dc.date.available | 2023-01-26T13:35:23Z | |
dc.date.issued | 2022-12-11 | |
dc.identifier.citation | Verdura, S... [et al.]. Silibinin Overcomes EMT-Driven Lung Cancer Resistance to New-Generation ALK Inhibitors. Cancers 2022, 14, 6101. [https://doi.org/10.3390/cancers14246101] | es_ES |
dc.identifier.uri | https://hdl.handle.net/10481/79391 | |
dc.description.abstract | 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 secondgeneration brigatinib and were fully refractory to third-generation lorlatinib. Such cross-resistance to new-generation ALK–TKIs, which was partially recapitulated upon chronic TGF 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 (TGF )/SMAD signaling pathway. Silibinin deactivated TGF -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 TGF 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 TGF 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 TGF /SMAD signaling axis in mesenchymal ALK-rearranged NSCLC cells. | es_ES |
dc.description.sponsorship | Ministry of Science and Innovation, Spain (MICINN) Spanish Government | es_ES |
dc.description.sponsorship | Plan Nacional de l+D+I PID2019-10455GB-I00 CP20/00003 Spanish Government | es_ES |
dc.description.sponsorship | Fundacio Oncolliga Girona (Lliga catalana d'ajuda al malalt de cancer, Girona) | es_ES |
dc.description.sponsorship | Spanish Government | es_ES |
dc.description.sponsorship | Center for Forestry Research & Experimentation (CIEF) | es_ES |
dc.description.sponsorship | European Commission PI22/00297 | es_ES |
dc.description.sponsorship | Grupo Espanol de Cancer de Pulmon (GECP) RTI2019-096724-B-C21 | es_ES |
dc.description.sponsorship | La Marato de TV3 foundation | es_ES |
dc.description.sponsorship | Health Research and Innovation Strategic Plan PROMETEO/2021/059 | es_ES |
dc.description.sponsorship | Pla strategic de recerca i innovacio en salut 201906 | es_ES |
dc.description.sponsorship | Generalitat de Catalunya | es_ES |
dc.description.sponsorship | Instituto de Salud Carlos III SLT006/17/114 | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | MDPI | es_ES |
dc.rights | Atribución 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject | ALK | es_ES |
dc.subject | Crizotinib | es_ES |
dc.subject | Brigatinib | es_ES |
dc.subject | Lorlatinib | es_ES |
dc.subject | Silibinin | es_ES |
dc.subject | EMT | es_ES |
dc.subject | TGF-beta | es_ES |
dc.subject | Lung cancer | es_ES |
dc.title | Silibinin Overcomes EMT-Driven Lung Cancer Resistance to New-Generation ALK Inhibitors | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | es_ES |
dc.identifier.doi | 10.3390/cancers14246101 | |
dc.type.hasVersion | info:eu-repo/semantics/publishedVersion | es_ES |