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2021
Logie, Emilie; Chirumamilla, Chandra S; Perez-Novo, Claudina; Shaw, Priyanka; Declerck, Ken; Palagani, Ajay; Rangarajan, Savithri; Cuypers, Bart; Neuter, Nicolas De; Turabe, Fazil Mobashar Hussain Urf; Verma, Navin Kumar; Bogaerts, Annemie; Laukens, Kris; Offner, Fritz; Vlierberghe, Pieter Van; Ostade, Xaveer Van; Berghe, Wim Vanden
In: Cancers, vol. 13, no. 7, 2021, ISSN: 2072-6694.
@article{cancers13071618,
title = {Covalent Cysteine Targeting of Bruton’s Tyrosine Kinase (BTK) Family by Withaferin-A Reduces Survival of Glucocorticoid-Resistant Multiple Myeloma MM1 Cells},
author = {Emilie Logie and Chandra S Chirumamilla and Claudina Perez-Novo and Priyanka Shaw and Ken Declerck and Ajay Palagani and Savithri Rangarajan and Bart Cuypers and Nicolas De Neuter and Fazil Mobashar Hussain Urf Turabe and Navin Kumar Verma and Annemie Bogaerts and Kris Laukens and Fritz Offner and Pieter Van Vlierberghe and Xaveer Van Ostade and Wim Vanden Berghe},
url = {https://www.mdpi.com/2072-6694/13/7/1618},
doi = {10.3390/cancers13071618},
issn = {2072-6694},
year = {2021},
date = {2021-01-01},
journal = {Cancers},
volume = {13},
number = {7},
abstract = {Multiple myeloma (MM) is a hematological malignancy characterized by plasma cells’ uncontrolled growth. The major barrier in treating MM is the occurrence of primary and acquired therapy resistance to anticancer drugs. Often, this therapy resistance is associated with constitutive hyperactivation of tyrosine kinase signaling. Novel covalent kinase inhibitors, such as the clinically approved BTK inhibitor ibrutinib (IBR) and the preclinical phytochemical withaferin A (WA), have, therefore, gained pharmaceutical interest. Remarkably, WA is more effective than IBR in killing BTK-overexpressing glucocorticoid (GC)-resistant MM1R cells. To further characterize the kinase inhibitor profiles of WA and IBR in GC-resistant MM cells, we applied phosphopeptidome- and transcriptome-specific tyrosine kinome profiling. In contrast to IBR, WA was found to reverse BTK overexpression in GC-resistant MM1R cells. Furthermore, WA-induced cell death involves covalent cysteine targeting of Hinge-6 domain type tyrosine kinases of the kinase cysteinome classification, including inhibition of the hyperactivated BTK. Covalent interaction between WA and BTK could further be confirmed by biotin-based affinity purification and confocal microscopy. Similarly, molecular modeling suggests WA preferably targets conserved cysteines in the Hinge-6 region of the kinase cysteinome classification, favoring inhibition of multiple B-cell receptors (BCR) family kinases. Altogether, we show that WA’s promiscuous inhibition of multiple BTK family tyrosine kinases represents a highly effective strategy to overcome GC-therapy resistance in MM.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Boullosa, Laurie Freire; Loenhout, Jinthe Van; Flieswasser, Tal; Waele, Jorrit De; Hermans, Christophe; Lambrechts, Hilde; Cuypers, Bart; Laukens, Kris; Bartholomeus, Esther; Siozopoulou, Vasiliki; Vos, Winnok H De; Peeters, Marc; Smits, Evelien L J; Deben, Christophe
In: Redox Biology, pp. 101949, 2021, ISSN: 2213-2317.
@article{BOULLOSA2021101949,
title = {Auranofin reveals therapeutic anticancer potential by triggering distinct molecular cell death mechanisms and innate immunity in mutant p53 non-small cell lung cancer},
author = {Laurie Freire Boullosa and Jinthe Van Loenhout and Tal Flieswasser and Jorrit De Waele and Christophe Hermans and Hilde Lambrechts and Bart Cuypers and Kris Laukens and Esther Bartholomeus and Vasiliki Siozopoulou and Winnok H De Vos and Marc Peeters and Evelien L J Smits and Christophe Deben},
url = {https://www.sciencedirect.com/science/article/pii/S2213231721000975},
doi = {https://doi.org/10.1016/j.redox.2021.101949},
issn = {2213-2317},
year = {2021},
date = {2021-01-01},
journal = {Redox Biology},
pages = {101949},
abstract = {Auranofin (AF) is an FDA-approved antirheumatic drug with anticancer properties that acts as a thioredoxin reductase 1 (TrxR) inhibitor. The exact mechanisms through which AF targets cancer cells remain elusive. To shed light on the mode of action, this study provides an in-depth analysis on the molecular mechanisms and immunogenicity of AF-mediated cytotoxicity in the non-small cell lung cancer (NSCLC) cell line NCI-H1299 (p53 Null) and its two isogenic derivates with mutant p53 R175H or R273H accumulation. TrxR is highly expressed in a panel of 72 NSCLC patients, making it a valid druggable target in NSCLC for AF. The presence of mutant p53 overexpression was identified as an important sensitizer for AF in (isogenic) NSCLC cells as it was correlated with reduced thioredoxin (Trx) levels in vitro. Transcriptome analysis revealed dysregulation of genes involved in oxidative stress response, DNA damage, granzyme A (GZMA) signaling and ferroptosis. Although functionally AF appeared a potent inhibitor of GPX4 in all NCI-H1299 cell lines, the induction of lipid peroxidation and consequently ferroptosis was limited to the p53 R273H expressing cells. In the p53 R175H cells, AF mainly induced large-scale DNA damage and replication stress, leading to the induction of apoptotic cell death rather than ferroptosis. Importantly, all cell death types were immunogenic since the release of danger signals (ecto-calreticulin, ATP and HMGB1) and dendritic cell maturation occurred irrespective of (mutant) p53 expression. Finally, we show that AF sensitized cancer cells to caspase-independent natural killer cell-mediated killing by downregulation of several key targets of GZMA. Our data provides novel insights on AF as a potent, clinically available, off-patent cancer drug by targeting mutant p53 cancer cells through distinct cell death mechanisms (apoptosis and ferroptosis). In addition, AF improves the innate immune response at both cytostatic (natural killer cell-mediated killing) and cytotoxic concentrations (dendritic cell maturation).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2020
Deben, Christophe; Boullosa, Laurie Freire; Domen, Andreas; Wouters, An; Cuypers, Bart; Laukens, Kris; Lardon, Filip; Pauwels, Patrick
Characterization of acquired nutlin-3 resistant non-small cell lung cancer cells Journal Article
In: Cancer Drug Resistance, vol. 3, pp. [Online First], 2020, ISSN: 2578-532X.
@article{Deben2020,
title = {Characterization of acquired nutlin-3 resistant non-small cell lung cancer cells},
author = {Christophe Deben and Laurie Freire Boullosa and Andreas Domen and An Wouters and Bart Cuypers and Kris Laukens and Filip Lardon and Patrick Pauwels},
url = {https://doi.org/10.20517/cdr.2020.91},
doi = {10.20517/cdr.2020.91},
issn = {2578-532X},
year = {2020},
date = {2020-01-01},
journal = {Cancer Drug Resistance},
volume = {3},
pages = {[Online First]},
abstract = {Aim: The purpose of this manuscript is to study the potential characteristics of acquired nutlin-3 resistant non-small cell lung cancer cells (NSCLC). Nutlin-3 is an inhibitor of the murine-double minute 2 protein, the main negative regulator of wild type p53, of which several derivatives are currently in clinical development.Methods: A549 NSCLC cells were exposed to increasing concentrations of nutlin-3 for a period of 18 weeks. Monoclonal derivates were cultured, and the most resistance subclone was selected for whole transcriptome analysis. Gene set enrichment analysis was performed on differentially expressed genes between A549 nutlin-3 resistant cancer cells and the parental A549 p53 wild type cancer cells. Relevant findings were validated at the gene, protein and/or functional level.Results: All nutlin-3 resistant subclones acquired mutations in the TP53 gene, resulting in overexpression of the mutant p53 protein. The most resistant subclone was enriched for genes related to epithelial to mesenchymal transition (EMT), resulting in increased migratory and invasive potential. Furthermore, these cells were enriched in genes related to inflammation, tissue remodelling, and angiogenesis. Importantly, expression of several immune checkpoints, including PD-L1 and PD-L2, was significantly upregulated, and cisplatin-induced cell death was reduced.Conclusion: Transcriptome analysis of a highly nutlin-3 resistant A549 subclone shows the relevance of studying (1) resistance to standard of care chemotherapy; (2) secretion of immunomodulating chemo- and cytokines; (3) immune checkpoint expression; and (4) EMT and invasion in nutlin-3 resistant cancer cells in addition to acquired mutations in the TP53 gene.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}