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Article

Covalent Cysteine Targeting of Bruton’s Tyrosine Kinase (BTK) Family by Withaferin-A Reduces Survival of Glucocorticoid-Resistant Multiple Myeloma MM1 Cells

1
Laboratory of Protein Science, Proteomics and Epigenetic Signaling (PPES) and Integrated Personalized and Precision Oncology Network (IPPON), Department of Biomedical Sciences, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, 2610 Wilrijk, Belgium
2
Plasma Lab for Applications in Sustainability and Medicine Antwerp (PLASMANT), Department of Chemistry, University of Antwerp, 2610 Wilrijk, Belgium
3
PamGene International B.V., 5211 Hertogenbosch, The Netherlands
4
Biomedical Informatics Network Antwerp (Biomina), Department of Informatics, University of Antwerp, 2610 Wilrijk, Belgium
5
Lymphocyte Signaling Research Laboratory, Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore 1308232, Singapore
6
Hematology, Department of Internal Medicine, Ghent University, 9000 Ghent, Belgium
7
Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Jean-Max Pasquet and Paulo De Sepulveda
Cancers 2021, 13(7), 1618; https://doi.org/10.3390/cancers13071618
Received: 1 March 2021 / Revised: 25 March 2021 / Accepted: 29 March 2021 / Published: 31 March 2021
(This article belongs to the Special Issue Protein Kinase in Leukemia)
Glucocorticoid therapy resistance in B-cell malignancies is often associated with constitutive activation of tyrosine kinases. Novel anticancer drugs targeting hyperactivated tyrosine kinases, such as Bruton’s tyrosine kinase (BTK), have, therefore, gained much interest over the past few decades and have already been approved for clinical use. In this study, we compared the therapeutic efficacy of the phytochemical kinase inhibitor withaferin A with the clinically approved BTK inhibitor ibrutinib to target hyperactivated tyrosine kinase signaling in glucocorticoid-resistant multiple myeloma cells. Our results demonstrate that withaferin A-induced cell death of glucocorticoid-resistant MM1R cells involves covalent cysteine targeting of multiple Hinge-6 domain type tyrosine kinases of the kinase cysteinome classification, including BTK.
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. View Full-Text
Keywords: withaferin A; BTK; multiple myeloma; therapy resistance; glucocorticoids; ibrutinib withaferin A; BTK; multiple myeloma; therapy resistance; glucocorticoids; ibrutinib
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MDPI and ACS Style

Logie, E.; Chirumamilla, C.S.; Perez-Novo, C.; Shaw, P.; Declerck, K.; Palagani, A.; Rangarajan, S.; Cuypers, B.; De Neuter, N.; Mobashar Hussain Urf Turabe, F.; Kumar Verma, N.; Bogaerts, A.; Laukens, K.; Offner, F.; Van Vlierberghe, P.; Van Ostade, X.; Berghe, W.V. Covalent Cysteine Targeting of Bruton’s Tyrosine Kinase (BTK) Family by Withaferin-A Reduces Survival of Glucocorticoid-Resistant Multiple Myeloma MM1 Cells. Cancers 2021, 13, 1618. https://doi.org/10.3390/cancers13071618

AMA Style

Logie E, Chirumamilla CS, Perez-Novo C, Shaw P, Declerck K, Palagani A, Rangarajan S, Cuypers B, De Neuter N, Mobashar Hussain Urf Turabe F, Kumar Verma N, Bogaerts A, Laukens K, Offner F, Van Vlierberghe P, Van Ostade X, Berghe WV. Covalent Cysteine Targeting of Bruton’s Tyrosine Kinase (BTK) Family by Withaferin-A Reduces Survival of Glucocorticoid-Resistant Multiple Myeloma MM1 Cells. Cancers. 2021; 13(7):1618. https://doi.org/10.3390/cancers13071618

Chicago/Turabian Style

Logie, Emilie, Chandra S. Chirumamilla, Claudina Perez-Novo, Priyanka Shaw, Ken Declerck, Ajay Palagani, Savithri Rangarajan, Bart Cuypers, Nicolas De Neuter, Fazil Mobashar Hussain Urf Turabe, Navin Kumar Verma, Annemie Bogaerts, Kris Laukens, Fritz Offner, Pieter Van Vlierberghe, Xaveer Van Ostade, and Wim V. Berghe. 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, no. 7: 1618. https://doi.org/10.3390/cancers13071618

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