Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/151836
Title: Covalent cysteine targeting of Bruton’s tyrosine kinase (BTK) family by withaferin-A reduces survival of glucocorticoid-resistant multiple myeloma MM1 cells
Authors: Logie, Emilie
Chirumamilla, Chandra S.
Perez-Novo, Claudina
Shaw, Priyanka
Declerck, Ken
Palagani, Ajay
Rangarajan, Savithri
Cuypers, Bart
De Neuter, Nicolas
Fazil, Mobashar Hussain Urf Turabe
Verma, Navin Kumar
Bogaerts, Annemie
Laukens, Kris
Offner, Fritz
Van Vlierberghe, Pieter
Van Ostade, Xaveer
Berghe, Wim Vanden
Keywords: Science::Medicine
Issue Date: 2021
Source: Logie, E., Chirumamilla, C. S., Perez-Novo, C., Shaw, P., Declerck, K., Palagani, A., Rangarajan, S., Cuypers, B., De Neuter, N., Fazil, M. H. U. T., Verma, N. K., Bogaerts, A., Laukens, K., Offner, F., Van Vlierberghe, P., Van Ostade, X. & Berghe, W. V. (2021). Covalent cysteine targeting of Bruton’s tyrosine kinase (BTK) family by withaferin-A reduces survival of glucocorticoid-resistant multiple myeloma MM1 cells. Cancers, 13(7), 1618-. https://dx.doi.org/10.3390/cancers13071618
Project: MOE2017-T2-2-004
OFLCG18May-0028
Journal: Cancers
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.
URI: https://hdl.handle.net/10356/151836
ISSN: 2072-6694
DOI: 10.3390/cancers13071618
Rights: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

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