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Cited by 41Lymphoma Diagnosis and TreatmentChronic Lymphocytic Leukemia ResearchCNS Lymphoma Diagnosis and Treatment

The resistance mechanisms and treatment strategies of BTK inhibitors in B-cell lymphoma

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Wang, Haoran, Zhang, Wentao, Yang, Jingyi, Zhou, Keshu·2021·Hematological Oncology
DOI 10.1002/hon.2933PMC PMC9293416
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Abstract

Bruton's tyrosine kinase inhibitors (BTKi) have revolutionized the treatment of B‐cell lymphoma (BCL). These drugs interfere with the mechanisms underlying malignant B‐cell pathophysiology, allowing better drug response as well as low toxicity. However, these multiple mechanisms also lead to drug resistance, which compromised the treatment outcome and needs to be solved urgently. This review focuses on genomic variations (such as BTK and its downstream PCLG2 mutations as well as Del 8p, 2p+, Del 6q/8p, BIRC3 , TRAF2 , TRAF3 , CARD11 , MYD88 , and CCND1 mutations) and related pathways (such as PI3K/Akt/mTOR, NF‐κB, MAPK signaling pathways, overexpression of B‐cell lymphoma 6, platelet‐derived growth factor, toll‐like receptors, and microenvironment, cancer stem cells, and exosomes) involved in cancer pathophysiology to discuss the mechanisms underlying resistance to BTKi. We have also reviewed the newly reported drug resistance mechanisms and the proposed potential treatment strategies (the next‐generation BTKi, proteolysis‐targeting chimera‐BTK, XMU‐MP‐3, PI3K‐Akt‐mTOR pathway, MYC or LYN kinase inhibitor, and other small‐molecule targeted drugs) to overcome drug resistance. The findings presented in this review lay a strong foundation for further research in this field.

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  • Approximately 20% of CLL patients who develop ibrutinib resistance are not found to have any BTK or PLCG2 mutations, even when using highly sensitive testing, suggesting alternate mechanisms of resistance.

    “Approximately 20% of CLL patients who develop ibrutinib resistance are not found to have any BTK or PLCG2 mutations, even when using highly sensitive testing, suggesting alternate mechanisms of resistance(38).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [38]

    The Genetic Mechanisms section (page not provided) reports that whole-exome sequencing found BTK or PLCG2 mutations in 80% of CLL patients with acquired ibrutinib resistance, supporting the approximate 20% figure. The De-regulated Pathways section (page not provided) discusses other resistance mechanisms. The paper does not say the mutations remained undetected even with highly sensitive testing. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Mutations outside of C481 have been less commonly associated with treatment resistance in patients treated with a cBTKi.

    “Mutations outside of C481 have been less commonly associated with treatment resistance in patients treated with a cBTKi (Figure 3) (38).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [38]

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Cited by

Sorted by citations

Authors
Wang, H., Zhang, W., Yang, J., & Zhou, K.
Affiliations
  • Zhengzhou University (CN)
  • Chinese People's Armed Police Force (CN)
Corresponding author
  • Yang, Jingyi
  • Zhou, Keshu
ORCID
Venue
Hematological Oncology
Publisher
Wiley
Published
2021-10-15
Volume
39
Issue
5
Pages
605-615
ISSN
  • 0278-0232 (ISSN-L)
  • 1099-1069
DOI
10.1002/hon.2933
PMC
PMC9293416
OpenAlex
W3207433478
Cited by
41
References
7
Citations by year
2026: 4 · 2025: 13 · 2024: 11 · 2023: 6 · 2022: 6 · 2021: 1
FWCI
1.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Hematological Oncology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
National Natural Science Foundation of China (81470336)
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
BTK inhibitors, B-cell lymphoma, drug resistance mechanisms, BTK mutations, MYD88 mutation, CARD11, PI3K/AKT/mTOR pathway, NF-κB signaling, MAPK signaling, platelet-derived growth factor, Toll-like receptors, tumor microenvironment, cancer stem cells, exosomes, PROTACs, MYC inhibitors
MeSH terms
Agammaglobulinaemia Tyrosine Kinase, Antineoplastic Agents, Humans, Prognosis, Lymphoma, B-Cell, Drug Resistance, Neoplasm, Molecular Targeted Therapy

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