Characterization of ibrutinib-sensitive and -resistant mantle lymphoma cells
Abstract
Ibrutinib inhibits Bruton tyrosine kinase (BTK), a key component of early B-cell receptor (BCR) signalling pathways. A multicentre phase 2 trial of ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL) demonstrated a remarkable response rate. However, approximately one-third of patients have primary resistance to the drug while other patients appear to lose response and develop secondary resistance. Understanding the molecular mechanisms underlying ibrutinib sensitivity is of paramount importance. In this study, we investigated cell lines and primary MCL cells that display differential sensitivity to ibrutinib. We found that the primary cells display a higher BTK activity than normal B cells and MCL cells show differential sensitivity to BTK inhibition. Genetic knockdown of BTK inhibits the growth, survival and proliferation of ibrutinib-sensitive but not resistant MCL cell lines, suggesting that ibrutinib acts through BTK to produce its anti-tumour activities. Interestingly, inhibition of ERK1/2 and AKT, but not BTK phosphorylation per se, correlates well with cellular response to BTK inhibition in cell lines as well as in primary tumours. Our study suggests that, to prevent primary resistance or to overcome secondary resistance to BTK inhibition, a combinatory strategy that targets multiple components or multiple pathways may represent the most effective approach.
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BTK is constitutively active in MCL, as p-BTK (Y223) levels were higher in primary MCL cells than in resting B cells.
“Importantly, BTK is constitutively active in this disease, as a recent study found that despite similar BTK expression levels, levels of p-BTK (Y223), a surrogate marker of BTK activity, were higher in primary MCL cells than in resting B cells.38”
From Bruton tyrosine kinase degradation as a therapeutic strategy for cancer (2019) · cites this paper as [38]
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Bruton tyrosine kinase degradation as a therapeutic strategy for cancer
Dobrovolsky, D., Wang, E. S., Morrow, S., Leahy, C., Faust, T., Nowak, R. P., Donovan, K. A., Yang, G., Li, Z., Fischer, E. S., et al. (2019) · Blood · doi:10.1182/blood-2018-07-862953 · Cited by 169 · see citing works
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Self-citationPromising efficacy of novel BTK inhibitor AC0010 in mantle cell lymphoma
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- Authors
- Ma, J., Lu, P., Guo, A., Cheng, S., Zong, H., Martin, P., Coleman, M., & Wang, Y. L.
- Affiliations
- Weill Cornell Medicine (US)
- University of Chicago (US)
- Corresponding author
- Wang, Y. Lynn
- Venue
- British Journal of Haematology
- Publisher
- Wiley
- Published
- 2014-06-24
- Volume
- 166
- Issue
- 6
- Pages
- 849-861
- ISSN
- 0007-1048 (ISSN-L)
- 1365-2141
- OpenAlex
- W1999824748
- Cited by
- 90
- References
- 38
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 6 · 2021: 16 · 2020: 12 · 2019: 8 · 2018: 13 · 2017: 6 · 2016: 12 · 2015: 10
- FWCI
- 6.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- British Journal of Haematology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Start up funding from my institutions: U. of Chicago and Weill Cornell Medical College
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Neurology › CNS Lymphoma Diagnosis and Treatment
- Keywords
- ibrutinib, mantle cell lymphoma, Bruton's tyrosine kinase, drug resistance, BTK inhibition, B cell receptor signaling, ERK1/2, Akt, combination therapy, relapsed/refractory lymphoma
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Adenine, Antineoplastic Agents, Cell Cycle, Cell Survival, Humans, Phosphorylation, Piperidines, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Tumor Cells, Cultured, Cell Death, Drug Resistance, Neoplasm, Lymphoma, Mantle-Cell, MAP Kinase Signaling System, Cell Proliferation, Gene Knockdown Techniques
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