Identification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL
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// Shruti Sharma 1, * , Natalie Galanina 2, * , Ailin Guo 1, * , Jimmy Lee 1 , Sabah Kadri 1, 3 , Charles Van Slambrouck 1 , Bradley Long 1 , Weige Wang 1 , Mei Ming 1 , Larissa V. Furtado 1 , Jeremy P. Segal 1 , Wendy Stock 2 , Girish Venkataraman 1 , Wei-Jen Tang 4 , Pin Lu 1 , Yue Lynn Wang 1 1 Department of Pathology, University of Chicago, Chicago, IL 60637, USA 2 Department of Medicine, University of Chicago, Chicago, IL 60637, USA 3 Center for Research Informatics, University of Chicago, Chicago, IL 60637, USA 4 Ben-May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA * These authors have contributed equally to this work Correspondence to: Yue Lynn Wang, email: ylwang@bsd.uchicago.edu Keywords: chronic lymphocytic leukemia, Richter transformation, ibrutinib resistance, BTK , molecular targeted therapy Received: June 04, 2016 Accepted: August 15, 2016 Published: September 10, 2016 ABSTRACT Ibrutinib (ibr), a first-in-class Bruton tyrosine kinase (BTK) inhibitor, has demonstrated high response rates in both relapsed/refractory and treatment naïve chronic lymphocytic leukemia (CLL). However, about 25% of patients discontinue ibrutinib therapy at a median follow-up of 20 months and many patients discontinue the treatment due to leukemia progression or Richter transformation. Mutations affecting the C481 residue of BTK disrupt ibrutinib binding and have been characterized by us and others as the most common mechanism of ibrutinib resistance. Thus far, all described BTK mutations are located in its kinase domain and mutations outside this domain have never been described. Herein, we report a patient whose CLL progressed, was salvaged with ibrutinib and then relapsed. Serial analysis of samples throughout patient’s clinical course identified a structurally novel mutation ( BTK T316A ) in the SH2 domain, but not kinase domain, of Bruton tyrosine kinase which was associated with disease relapse. Functionally, cells carrying BTK T316A show resistance to ibrutinib at both cellular and molecular levels to a similar extent as BTK C481S . Our study lends further insight into the diverse mechanisms of ibrutinib resistance that has important implications for the development of next-generation BTK inhibitors as well as mutation detection in relapsed patients.
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BTK T316A affect a binding residue for B-cell like linker protein, preventing activation of the downstream PLCγ2.
“BTK T316A affect a binding residue for B-cell like linker protein, preventing activation of the downstream PLCγ2(28).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [28]
The Discussion places T316A in BTK’s SH2 domain and predicts that it may lessen binding to B-cell linker protein. But it reports that stimulated PLCG2 activity was comparable in cells with wild-type and mutant BTK, contrary to the claim that T316A prevents downstream PLCγ2 activation. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIn published studies of disease progression during BTKi therapy, approximately 35% of patients were found to have a BTK mutation alone, an additional 10% had coexisting mutations in PLCG2, 5% had a PLCG2 mutation alone, and the remaining 50% were wild-type for BTK and PLCG2.
“In published studies of disease progression during BTKi therapy,approximately 35% of patients were found to have aBTK mutation alone, an additional 10% had a coexisting mutations in PLCG2, 5% of cases had a PLCG2mutation alone, and the remaining 50% were wild-type (WT) for BTK and PLCG2 (Figure 2)(12, 19, 21–31).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [28]
The Introduction identifies BTK and PLCG2 mutations in ibrutinib resistance, and the Discussion says some relapsed CLL patients carry neither. The Results describe a BTK mutation in the patient studied. No passage gives the claimed 35%/10%/5%/50% breakdown or establishes the frequencies of coexisting and PLCG2-only mutations. (LLM, conf=0.85)
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“BTK t316A affect a binding residue for B-cell like linker protein, preventing activation of the downstream Plcγ2 [27]. in addition, several mutations in the BtK kinase domain such as l528w, M437R, and v416l demonstrate greatly reduced BtK enzymatic function [40].”
- Authors
- Sharma, S., Galanina, N., Guo, A., Lee, J., Kadri, S., Van Slambrouck, C., Long, B., Wang, W., Ming, M., Furtado, L. V., Segal, J. P., Stock, W., Venkataraman, G., Tang, W.-J., Lu, P., & Wang, Y. L.
- Affiliations
- University of Chicago (US)
- Department of Pathology, University of Chicago, Chicago, IL 60637, USA
- Corresponding author
- Sharma, Shruti
- Galanina, Natalie
- Guo, Ailin
- ORCID
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2016-09-10
- Volume
- 7
- Issue
- 42
- Pages
- 68833-68841
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC5356593
- OpenAlex
- W2514938762
- Cited by
- 90
- References
- 5
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 12 · 2023: 6 · 2022: 10 · 2021: 11 · 2020: 9 · 2019: 13 · 2018: 6 · 2017: 11 · 2016: 1
- FWCI
- 7.50
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Keywords
- Bruton's tyrosine kinase, chronic lymphocytic leukemia, Richter transformation, kinase domain mutations, recurrence, relapsed/refractory CLL, minimal residual disease
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Adenine, Antineoplastic Agents, Cell Transformation, Neoplastic, DNA Mutational Analysis, Female, Humans, Middle Aged, Mutation, Neoplasm Recurrence, Local, Piperidines, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Leukemia, Lymphocytic, Chronic, B-Cell, src Homology Domains, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, High-Throughput Nucleotide Sequencing
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