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

(2021) CANCERS. 13(7).
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Abstract
Simple Summary 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.
Keywords
withaferin A, BTK, multiple myeloma, therapy resistance, glucocorticoids, ibrutinib

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MLA
Logie, Emilie, et al. “Covalent Cysteine Targeting of Bruton’s Tyrosine Kinase (BTK) Family by Withaferin-A Reduces Survival of Glucocorticoid-Resistant Multiple Myeloma MM1 Cells.” CANCERS, vol. 13, no. 7, 2021, doi:10.3390/cancers13071618.
APA
Logie, E., Chirumamilla, C. S., Perez-Novo, C., Shaw, P., Declerck, K., Palagani, A., … 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). https://doi.org/10.3390/cancers13071618
Chicago author-date
Logie, Emilie, Chandra S. Chirumamilla, Claudina Perez-Novo, Priyanka Shaw, Ken Declerck, Ajay Palagani, Savithri Rangarajan, et al. 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). https://doi.org/10.3390/cancers13071618.
Chicago author-date (all authors)
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 Vanden 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 (7). doi:10.3390/cancers13071618.
Vancouver
1.
Logie E, Chirumamilla CS, Perez-Novo C, Shaw P, Declerck K, Palagani A, et al. 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).
IEEE
[1]
E. Logie et al., “Covalent cysteine targeting of Bruton’s tyrosine kinase (BTK) family by withaferin-A reduces survival of glucocorticoid-resistant multiple myeloma MM1 cells,” CANCERS, vol. 13, no. 7, 2021.
@article{8711103,
  abstract     = {{Simple Summary 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.}},
  articleno    = {{1618}},
  author       = {{Logie, Emilie and Chirumamilla, Chandra S. and Perez-Novo, Claudina and Shaw, Priyanka and Declerck, Ken and Palagani, Ajay and Rangarajan, Savithri and Cuypers, Bart and De Neuter, Nicolas and Mobashar Hussain Urf Turabe, Fazil and Kumar Verma, Navin and Bogaerts, Annemie and Laukens, Kris and Offner, Fritz and Van Vlierberghe, Pieter and Van Ostade, Xaveer and Berghe, Wim Vanden}},
  issn         = {{2072-6694}},
  journal      = {{CANCERS}},
  keywords     = {{withaferin A,BTK,multiple myeloma,therapy resistance,glucocorticoids,ibrutinib}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{22}},
  title        = {{Covalent cysteine targeting of Bruton's tyrosine kinase (BTK) family by withaferin-A reduces survival of glucocorticoid-resistant multiple myeloma MM1 cells}},
  url          = {{http://dx.doi.org/10.3390/cancers13071618}},
  volume       = {{13}},
  year         = {{2021}},
}

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