@misc{10481/79391,
year = {2022},
month = {12},
url = {https://hdl.handle.net/10481/79391},
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.},
organization = {Ministry of Science and Innovation, Spain (MICINN)
Spanish Government},
organization = {Plan Nacional de l+D+I	PID2019-10455GB-I00	
CP20/00003	
Spanish Government},
organization = {Fundacio Oncolliga Girona (Lliga catalana d'ajuda al malalt de cancer, Girona)},
organization = {Spanish Government},
organization = {Center for Forestry Research & Experimentation (CIEF)},
organization = {European Commission	PI22/00297},
organization = {Grupo Espanol de Cancer de Pulmon (GECP)	RTI2019-096724-B-C21},
organization = {La Marato de TV3 foundation},
organization = {Health Research and Innovation Strategic Plan	PROMETEO/2021/059},
organization = {Pla strategic de recerca i innovacio en salut	201906},
organization = {Generalitat de Catalunya},
organization = {Instituto de Salud Carlos III		
SLT006/17/114},
publisher = {MDPI},
keywords = {ALK},
keywords = {Crizotinib},
keywords = {Brigatinib},
keywords = {Lorlatinib},
keywords = {Silibinin},
keywords = {EMT},
keywords = {TGF-beta},
keywords = {Lung cancer},
title = {Silibinin Overcomes EMT-Driven Lung Cancer Resistance to New-Generation ALK Inhibitors},
doi = {10.3390/cancers14246101},
author = {Verdura, Sara and Segura Carretero, Antonio},
}