Covalent cysteine targeting of Bruton’s tyrosine kinase (BTK) family by withaferin-A reduces survival of glucocorticoid-resistant multiple myeloma MM1 cells

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...

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Main 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
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
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Language:English
Published: 2021
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Online Access:https://hdl.handle.net/10356/151836
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Institution: Nanyang Technological University
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spelling sg-ntu-dr.10356-1518362023-03-05T16:47:42Z Covalent cysteine targeting of Bruton’s tyrosine kinase (BTK) family by withaferin-A reduces survival of glucocorticoid-resistant multiple myeloma MM1 cells 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 Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Withaferin A Bruton’s Tyrosine Kinase 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. Ministry of Education (MOE) Ministry of Health (MOH) National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This research was funded by Foundation Against Cancer (Belgium), grant number 7872, Hercules Foundation, grant number AUHA/13/012 and Research Foundation Flanders, grant number FWO G1179120N, G059713N. N.K.V. acknowledges funding support from the Singapore Ministry of Education (MOE) under its MOE Academic Research Fund (AcRF) Tier 2 Grant (grant number MOE2017-T2-2-004) and the National Research Foundation Singapore under its Open Fund Large Collaborative Grant (grant number OFLCG18May-0028) and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC). 2021-08-27T08:51:43Z 2021-08-27T08:51:43Z 2021 Journal Article 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 2072-6694 https://hdl.handle.net/10356/151836 10.3390/cancers13071618 33807411 2-s2.0-85103341843 7 13 1618 en MOE2017-T2-2-004 OFLCG18May-0028 Cancers © 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/). application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Medicine
Withaferin A
Bruton’s Tyrosine Kinase
spellingShingle Science::Medicine
Withaferin A
Bruton’s Tyrosine Kinase
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
Covalent cysteine targeting of Bruton’s tyrosine kinase (BTK) family by withaferin-A reduces survival of glucocorticoid-resistant multiple myeloma MM1 cells
description 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.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
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
format Article
author 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
author_sort Logie, Emilie
title Covalent cysteine targeting of Bruton’s tyrosine kinase (BTK) family by withaferin-A reduces survival of glucocorticoid-resistant multiple myeloma MM1 cells
title_short Covalent cysteine targeting of Bruton’s tyrosine kinase (BTK) family by withaferin-A reduces survival of glucocorticoid-resistant multiple myeloma MM1 cells
title_full Covalent cysteine targeting of Bruton’s tyrosine kinase (BTK) family by withaferin-A reduces survival of glucocorticoid-resistant multiple myeloma MM1 cells
title_fullStr Covalent cysteine targeting of Bruton’s tyrosine kinase (BTK) family by withaferin-A reduces survival of glucocorticoid-resistant multiple myeloma MM1 cells
title_full_unstemmed Covalent cysteine targeting of Bruton’s tyrosine kinase (BTK) family by withaferin-A reduces survival of glucocorticoid-resistant multiple myeloma MM1 cells
title_sort covalent cysteine targeting of bruton’s tyrosine kinase (btk) family by withaferin-a reduces survival of glucocorticoid-resistant multiple myeloma mm1 cells
publishDate 2021
url https://hdl.handle.net/10356/151836
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