Ibrutinib significantly inhibited Bruton’s tyrosine kinase (BTK) phosphorylation,<i>in-vitro</i> proliferation and enhanced overall survival in a preclinical Burkitt lymphoma (BL) model

Chu, Yaya; Lee, Sanghoon; Shah, Tishi; Yin, Changhong; Barth, Matthew J.; Miles, Rodney R.; Ayello, Janet; Morris, Erin; Harrison, Lauren; Ven, Carmella van de; Galardy, Paul J.; Goldman, Stanton; Lim, Megan S.; Hermiston, Michelle L.; McAllister-Lucas, Linda M.; Giulino‐Roth, Lisa; Perkins, Sherrie L.; Cairo, Mitchell S.

doi:10.1080/2162402x.2018.1512455

Cited by 19 publications

(21 citation statements)

References 50 publications

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“…Similar WA-specific changes could also be observed in U266 cells, another GC-resistant multiple myeloma cell line sensitive to WA treatment ( Figure 3 b,c and Figure S5 ). In line with previous studies [ 60 , 61 , 62 ], we did not observe any changes in BTK expression after the IBR treatment of MM1R cells indicating that IBR mainly targets BTK (hyper)phosphorylation and not total BTK protein levels ( Supplementary Figure S6 ).…”

Section: Resultssupporting

confidence: 92%

“…In this respect, partially reversible covalent binding characteristics of WA may promote more promiscuous tyrosine kinase targeting than IBR and explain the higher efficacy of WA than IBR in overcoming MM drug resistance. Finally, WA-mediated inhibition of BTK kinase activity was also accompanied by a time-dependent decrease in BTK mRNA and protein expression, not observed for IBR, suggesting that WA targets BTK hyperactivation at multiple levels [ 62 ]. For example, WA may indirectly decrease BTK activity by reducing kinase protein levels by inhibition of Sp1-dependent transcription [ 78 ], by post-transcriptional microRNA silencing mechanisms [ 53 , 79 ], or by decreasing kinase stability via heat shock chaperone proteins [ 45 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

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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

Logie

Chirumamilla

Pérez-Novo

et al. 2021

Cancers

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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.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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

Logie

Chirumamilla

Pérez-Novo

et al. 2021

Cancers

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“…Previous researches had showed high expression level of BTK phosphorylation in B cell lymphoma, which represented BTK activation and had correlation with lymphoma development [ 40 ]. BTKis inhibited BTK phosphorylation will inhibit lymphoma cells proliferation and increase overall survival in preclinical Burkitt lymphoma, and this effect could be enhanced by rituximab [ 41 ]. It is well known that constitutive activation of NFκB pathway is known as a hallmark of non-GCB-DLBCL, inhibition of NFκB induces apoptosis in different DLBCL cell lines, specifically in non-GCB-DLBCL [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of cylindromatosis protein phosphorylation by BTK inhibitor promotes apoptosis of non-GCB-diffuse large B-cell lymphoma

Wei

Zhong

et al. 2021

Cancer Cell Int

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Background Non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB-DLBCL) has worse clinical outcome than GCB-DLBCL, and some relapsed/refractory non-GCB-DLBCL (R/R non-GCB-DLBCL) are even resistant to CD20 monoclonal antibody (rituximab). Bruton’s tyrosine kinase inhibitors (BTKis) are new drugs for B-cell lymphoma. BTKis can promote apoptosis of DLBCL by inactivating nuclear transcription factor κB (NFκB) signaling pathway. Cylindromatosis (CYLD) is a tumor suppressor and ubiquitinase. CYLD can inactivate NFκB signaling pathway through ubiquitination and regulate the apoptosis of hematological tumors. The ubiquitination of CYLD can be regulated by phosphorylation, suggesting that the regulation of CYLD phosphorylation can be a potential mechanism to promote the apoptosis of hematological tumors. Therefore, we hypothesized that BTKis could promote the apoptosis of non-GCB-DLBCL by regulating the phosphorylation of CYLD, especially in rituximab resistant cases, and we proved this hypothesis through both in vivo and in vitro experiments. Methods The baseline expression levels of CYLD phosphorylation in non-GCB-DLBCL patients and cell lines were detected by Western Blotting. The non-GCB-DLBCL cell lines were treated with BTKis, and apoptosis induced by BTKis treatment was detected by Western blotting, cell viability assay and Annexin V assay. To verify whether the effect of BTKis on apoptosis in non-GCN-DLBCL cells is CYLD dependent, the expression of CYLD was knocked down by lentiviral shRNAs. To verify the effect of BTKis on the phosphorylation of CYLD and the apoptosis in vivo and in rituximab resistant non-GCB-DLBCL, the xeograft model and rituximab resistant non-GCB-DLBCL cells were generated by tumor cell inoculation and escalation of drug concentrations, respectively. Results BTKis induced apoptosis by down-regulating CYLD phosphorylationin in non GCB-DLBCL, xenograft mouse model, and rituximab-resistant cells, and this effect could be enhanced by rituximab. Knocking-down CYLD reversed apoptosis which was induced by BTKis. BTKis induced CYLD-dependent apoptosis in non-GCB-DLBCL including in rituximab-resistant cells. Conclusions The present results indicated that CYLD phosphorylation is a potential clinical therapeutic target for non-GCB-DLBCL, especially for rituximab-resistant relapsed/refractory cases.

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“…Ibrutinib has shown efficacy in r/r adult‐activated B‐cell like (ABC)‐DLBCL as a single agent (Wilson et al , 2015) and in combination with R‐ICE (Sauter et al , 2018). Ibrutinib has shown significant activity in pre‐clinical BL models (Nayyar et al , 2018; Chu et al , 2018). An ongoing international study (NCT02703272) in CAYA r/r B‐NHL is evaluating the efficacy of ibrutinib in combination with rituximab‐containing regimens [R‐ICE or R‐VICI (rituximab, vincristine, idarubicin, carboplatin, ifosfamide)].…”

Section: Novel Therapiesmentioning

confidence: 99%

Treatment of relapsed/refractory paediatric aggressive B‐cell non‐Hodgkin lymphoma

2020

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Summary Aggressive B‐cell non‐Hodgkin lymphoma (B‐NHL) accounts for ≈60% of NHL in children/adolescents. In newly diagnosed Burkitt lymphoma and diffuse large B‐cell lymphoma, short intensive multiagent chemotherapy is associated with a five‐year event‐free survival of around 90%. Very few children/adolescents with aggressive B‐NHL show a relapsed/refractory (r/r) disease. The outcome is poor, with cure rates <30%, and there is no standard of care. Rituximab‐containing salvage regimens may provide a complete/partial response in 60–70% of cases. However, long‐term survival is <10% for non‐transplanted patients. Autologous or allogeneic haematopoietic stem cell transplant is, nowadays, the best option for responding patients, with survival rates around 50%. The benefit of autologous versus allogeneic HSCT is not clear. Numerous novel therapies for r/r B‐NHL are currently being tested in adults, including next‐generation monoclonal antibodies, novel cellular therapy strategies and therapies directed against new targets. Some are under investigation also in children/adolescents, with promising preliminary results.

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Ibrutinib significantly inhibited Bruton’s tyrosine kinase (BTK) phosphorylation,in-vitro proliferation and enhanced overall survival in a preclinical Burkitt lymphoma (BL) model

Cited by 19 publications

References 50 publications

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

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

Down-regulation of cylindromatosis protein phosphorylation by BTK inhibitor promotes apoptosis of non-GCB-diffuse large B-cell lymphoma

Treatment of relapsed/refractory paediatric aggressive B‐cell non‐Hodgkin lymphoma

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