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Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib
Open accessAbstract
BACKGROUND: Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL). Resistance to irreversible kinase inhibitors and resistance associated with BTK inhibition have not been characterized. Although only a small proportion of patients have had a relapse during ibrutinib therapy, an understanding of resistance mechanisms is important. We evaluated patients with relapsed disease to identify mutations that may mediate ibrutinib resistance. METHODS: We performed whole-exome sequencing at baseline and the time of relapse on samples from six patients with acquired resistance to ibrutinib therapy. We then performed functional analysis of identified mutations. In addition, we performed Ion Torrent sequencing for identified resistance mutations on samples from nine patients with prolonged lymphocytosis. RESULTS: We identified a cysteine-to-serine mutation in BTK at the binding site of ibrutinib in five patients and identified three distinct mutations in PLCγ2 in two patients. Functional analysis showed that the C481S mutation of BTK results in a protein that is only reversibly inhibited by ibrutinib. The R665W and L845F mutations in PLCγ2 are both potentially gain-of-function mutations that lead to autonomous B-cell-receptor activity. These mutations were not found in any of the patients with prolonged lymphocytosis who were taking ibrutinib. CONCLUSIONS: Resistance to the irreversible BTK inhibitor ibrutinib often involves mutation of a cysteine residue where ibrutinib binding occurs. This finding, combined with two additional mutations in PLCγ2 that are immediately downstream of BTK, underscores the importance of the B-cell-receptor pathway in the mechanism of action of ibrutinib in CLL. (Funded by the National Cancer Institute and others.).
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TL;DR
Acquired resistance to ibrutinib in CLL often involves BTK C481S or PLCγ2 mutations that restore B-cell–receptor signaling. Functional studies show C481S prevents irreversible BTK binding, while PLCγ2 R665W/L845F are gain-of-function and BTK-independent.
Key findings
- Whole-exome sequencing of six patients with acquired ibrutinib resistance identified BTK C481S in five patients and PLCγ2 mutations in two patients: R665W in Patient 6, and R665W, L845F, plus S707Y in one patient who also had low-frequency BTK C481S.
- C481S BTK had lower ibrutinib affinity than nonmutant BTK (dissociation constant, 0.2 nM vs. 10.4 nM) and was only reversibly inhibited by ibrutinib; washout experiments in patient cells showed inhibition required continuous drug exposure.
- PLCγ2 R665W and L845F showed enhanced anti-IgM–mediated calcium flux that was not inhibited by ibrutinib, indicating potential gain-of-function mutations allowing BTK-independent B-cell–receptor signaling.
- No BTK or PLCγ2 mutations were found in nine patients with prolonged lymphocytosis (≥12 months) on ibrutinib; sequencing depth was >700 reads for BTK C481 and PLCγ2 R665/S707 and >100 reads for PLCγ2 L845.
Methods
- Whole-exome sequencing was performed on baseline and relapse samples from six patients with acquired resistance to ibrutinib; relapse-specific nonsynonymous mutations were verified by Sanger or Ion Torrent sequencing.
- Ion Torrent sequencing was used to test for BTK and PLCγ2 mutations in nine patients with prolonged lymphocytosis during ibrutinib therapy.
- Functional analyses included in vitro kinase assays, flow cytometry, immunoblot assays, and stable transfection into DT40 or HEK 293T cells; statistical methods were detailed in the Supplementary Appendix.
Limitations
- The paper states that inability to identify small numbers of mutant clones in the presence of large numbers of nonmutant clones may mean such variants were present but not identified; the clinical significance of very low baseline R665W variant reads is unknown and more patients need evaluation.
- The paper states that other resistance mechanisms are likely present in a subgroup of patients without B-cell–receptor pathway mutations, and work is ongoing to identify alternative mechanisms.
- Evident from the text: the study is based on a small number of patients (six with acquired resistance and nine with prolonged lymphocytosis), limiting generalizability and statistical power.
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Claims the paper makes
22 Own result · 20 Own interpretation · 6 Partly supported · 4 Supported · 2 Couldn’t confirm · 2 No full text of the sources · 2 Own method · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In patients treated with ibrutinib, a characteristic lymphocytosis develops as CLL cells are mobilized from lymph nodes and the spleen.”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > ABSENCE OF BTK OR PLCγ2 MUTATIONS IN PATIENTS WITH PROLONGED LYMPHOCYTOSIS DURING IBRUTINIB THERAPY
What the sources say
- Partly supportedcites [24] sourceExperimental — accuracy not yet measured
The Results report that lymphocytosis occurred in 77% of patients treated with ibrutinib, and the Introduction describes cell mobilization from nodal and marrow sites as a possible mechanism. Our copy does not identify the spleen as a source of the mobilized CLL cells, so that part of the claim is unsupported. (LLM, conf=0.85)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Although lymphocytosis typically resolves within 8 months, a subgroup of patients have lymphocytosis that lasts longer than 12 months in the presence of a continued response to ibrutinib.24”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > ABSENCE OF BTK OR PLCγ2 MUTATIONS IN PATIENTS WITH PROLONGED LYMPHOCYTOSIS DURING IBRUTINIB THERAPY
What the sources say
- Supportedcites [24] source
The Results (page not specified) report a median time to lymphocyte normalization of 6.2 months and identify patients who still had lymphocytosis at 12 months but otherwise met criteria for a partial response. A second Results passage reports that their progression-free survival was not inferior to that of patients with a conventional partial or complete response. (LLM, conf=0.91)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“whereas dasatinib, a reversible inhibitor of BTK,23 inhibited nonmutant and mutant BTK with similar efficacy.”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > REVERSIBLE INHIBITION OF MUTANT BTK BY IBRUTINIB IN VITRO AND IN PATIENTS
What the sources say
- Partly supportedcites [23] sourceExperimental — accuracy not yet measured
The citation is attached to the description of dasatinib as a reversible BTK inhibitor. The Results establish that dasatinib inhibits BTK, but our copy does not establish that its inhibition is reversible. It also does not test C481S or support the sentence’s comparison of C481S with nonmutant BTK; the mutant it tests is T474I, which was resistant. (LLM, conf=0.83)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL).”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > Abstract > BACKGROUND
What the sources say
- Partly supportedcites [6] sourceExperimental — accuracy not yet measured
The section on PCI-32765-induced cytotoxicity states that PCI-32765 is an irreversible BTK inhibitor. Our copy does not name ibrutinib or establish that it is the same compound, so it does not fully support the claim as worded. (LLM, conf=0.78)
- Partly supportedcites [8] sourceExperimental — accuracy not yet measured
The Introduction states that PCI-32765 binds irreversibly to BTK, supporting the inhibitor property. Our copy does not identify PCI-32765 as ibrutinib, so it does not establish that the named drug has that property. (LLM, conf=0.76)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“At 26 months, the estimated progression-free survival rate among patients treated with ibrutinib is 75%.9”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > Abstract > CONCLUSIONS
What the sources say
- Supportedcites [9] source
The Results > Efficacy passage reports that the 26-month estimated progression-free survival rate during ibrutinib treatment was 75%, exactly as claimed. This estimate concerns the patients in the cited study. (LLM, conf=0.95)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Ibrutinib irreversibly binds BTK at the C481 residue, rendering it kinase-inactive”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > Abstract > CONCLUSIONS
What the sources say
- Partly supportedcites [6] sourceExperimental — accuracy not yet measured
The Introduction and Discussion describe PCI-32765 as an irreversible BTK inhibitor, and the section on BCR-dependent signaling reports reduced BTK phosphorylation consistent with inhibited kinase activity. Our copy does not identify PCI-32765 as ibrutinib or state that it binds BTK at C481, so those specifics are not established by this source. (LLM, conf=0.84)
- Partly supportedcites [8] sourceExperimental — accuracy not yet measured
The Introduction (page not provided) says PCI-32765 binds irreversibly to a cysteine residue in BTK and inhibits its enzymatic activity. It does not identify that residue as C481; a search for “C481” found no matching passage. The copy calls the drug PCI-32765 rather than ibrutinib. (LLM, conf=0.87)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“At relapse, none of the patients had mutations in other kinases containing a cysteine residue homologous to C481 in BTK that are irreversibly inhibited by ibrutinib”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > MUTATIONS IN BTK AND PLCγ2 REVEALED BY WHOLE-EXOME SEQUENCING
What the sources say
- Could not verifycites [7] sourceExperimental — accuracy not yet measured
The Results and Discussion describe PCI-32765 binding to BTK at Cys-481 and note that a small subset of other kinases has a homologous cysteine. Neither section reports sequencing patients at relapse or whether any had mutations in those kinases; searches for relapse and patient mutations found no such result in our copy. (LLM, conf=0.76)
- Could not verifycites [22] sourceExperimental — accuracy not yet measured
The Introduction and Results describe cysteine-dependent irreversible inhibition of BTK and ITK, but do not report mutation testing at relapse. A search for relapsed patients, six patients, and mutations in other kinases found no passage addressing the claim. (LLM, conf=0.75)
plainn = 6- Asserted: passes — The authors put it forward as true.
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- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“mutations have not been observed in these other targets, findings that suggest that BTK is its critical target.”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > DISCUSSION
What the sources say
- Partly supportedcites [7] sourceExperimental — accuracy not yet measured
The Discussion reports that BTK inhibition correlated with efficacy in a mouse arthritis model, consistent with BTK being a relevant target in vivo. It does not report acquired-resistance mutations in patients or establish that mutations were absent from ITK, BLK, or other targets. It also says a role for other cysteine-containing kinases cannot be ruled out. (LLM, conf=0.80)
- Could not verifycites [22] sourceExperimental — accuracy not yet measured
The Results describe ITK-C442A engineered in Jurkat cells to test ibrutinib binding, not mutations observed in patients with acquired resistance. Searches for acquired-resistance mutations in ITK, BLK, and other targets found no passage addressing whether such mutations were observed; our copy therefore cannot verify the attributed claim. (LLM, conf=0.73)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“We have previously documented by immunoblot analysis24 that BTK and PLCγ2 are inhibited in these patients”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > DISCUSSION
What the sources say
- Supportedcites [24] source
The Results report immunoblot analysis of samples from patients with prolonged lymphocytosis at baseline and six months into ibrutinib therapy. BTK autophosphorylation was down-regulated in 8 of 8 patients, and PLCγ2 phosphorylation was diminished in 7 of 9; the authors conclude that both remain inhibited in most patients with persistent lymphocytosis. (LLM, conf=0.95)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Although ibrutinib inhibits other similar kinases that contain C481, including ITK and BLK,7,22”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > DISCUSSION
What the sources say
- Partly supportedcites [7] sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) says PCI-32765 binds BTK at Cys-481 and that inhibition of other cysteine-containing kinases, including BLK, cannot be ruled out. It does not establish BLK inhibition or identify ITK as a kinase inhibited by PCI-32765, so the claim is stronger and more specific than this paper supports. (LLM, conf=0.86)
- Partly supportedcites [22] sourceExperimental — accuracy not yet measured
The Results confirm that ibrutinib binds and inhibits ITK, but identify its covalent binding residue as C442, not C481. The passages searched for BLK do not report BLK inhibition, so the source does not support that part of the claim. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
- It may state two separate claims as one. 11
- The quote only partly states this claim. 2
- Probably not a substantial claim. 1
Every source the paper cites for this claim was checked and supports it.
In the paper
“Ibrutinib has been shown to have clinically significant activity in patients with relapsed CLL, with 71% of patients having an objective complete or partial response and an additional 15 to 20% of patients having a partial response with persistent lymphocytosis.”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > Abstract > CONCLUSIONS
What the sources say
- Supportedcites [9] source
The Results > Efficacy passage reports a 71% response rate by standard criteria in each dose cohort. It also reports an additional partial response with persistent lymphocytosis in 20% of the 420-mg cohort and 15% of the 840-mg cohort, matching the cited claim about patients with relapsed CLL. (LLM, conf=0.94)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“This mutation is not known to cause the X-linked agammaglobulinemia phenotype31 but instead results in retained catalytic activity.”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > DISCUSSION
What the sources say
- Could not verifycites [31] sourceExperimental — accuracy not yet measured
The citation is attached to the claim that C481S is not known to cause the X-linked agammaglobulinemia phenotype. The Mutation Statistics section discusses tolerated substitutions generally, but our copy does not address C481S specifically (searched: C481S, 481, and the phenotype claim). The retained-catalytic-activity clause falls after the citation and is not assessed as attributed to this source. (LLM, conf=0.72)
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Could not verify
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In Patients 3, 5, and 6, Ion Torrent sequencing was performed, and no mutation was identified in more than 0.2% of reads”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > MUTATIONS IN BTK AND PLCγ2 REVEALED BY WHOLE-EXOME SEQUENCING
plain- Asserted: passes — The authors put it forward as true.
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The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In Patient 6, the decrease in BTK phosphorylation at the time of the relapse was similar to the decrease at 11 months of therapy, when the patient was having a response to the drug (Fig. 3A), whereas PLCγ2 showed enhanced phosphorylation at the time of relapse”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > IDENTIFIED MUTATIONS IN PLCγ2 AS RESISTANCE MECHANISMS IN VITRO AND IN PATIENTS
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Ibrutinib washout experiments showed that the C481S mutation allows reversible, but not irreversible, inhibition of BTK by ibrutinib”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > REVERSIBLE INHIBITION OF MUTANT BTK BY IBRUTINIB IN VITRO AND IN PATIENTS
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At baseline, BTK phosphorylation was completely abrogated by ibrutinib with either washout or continuous exposure to ibrutinib. At the time of relapse, however, ibrutinib inhibited BTK phosphorylation only with continuous exposure”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > REVERSIBLE INHIBITION OF MUTANT BTK BY IBRUTINIB IN VITRO AND IN PATIENTS
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“After ibrutinib was discontinued, ibrutinib still inhibited BTK phosphorylation (Fig. 3C) but not PLCγ2 phosphorylation (Fig. 3D).”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > IDENTIFIED MUTATIONS IN PLCγ2 AS RESISTANCE MECHANISMS IN VITRO AND IN PATIENTS
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The intrinsic affinity of ibrutinib for nonmutant BTK was significantly higher than for mutant BTK (dissociation constant, 0.2 nM vs. 10.4 nM)”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > REVERSIBLE INHIBITION OF MUTANT BTK BY IBRUTINIB IN VITRO AND IN PATIENTS
plaincorrelational- Asserted: passes — The authors put it forward as true.
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The quote only partly states this claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data show that the R665W and L845F mutations in PLCγ2 are potentially gain-of-function mutations in the presence of B-cell–receptor stimulation and could be relevant as mutations conferring resistance to ibrutinib in patients.”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > IDENTIFIED MUTATIONS IN PLCγ2 AS RESISTANCE MECHANISMS IN VITRO AND IN PATIENTS
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The sequencing depth for BTK at C481 and for PLCγ2 at R665 and S707 was more than 700 reads, and the sequencing depth for PLCγ2 at L845 was more than 100 reads.”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > RESULTS > ABSENCE OF BTK OR PLCγ2 MUTATIONS IN PATIENTS WITH PROLONGED LYMPHOCYTOSIS DURING IBRUTINIB THERAPY
plainn = 9- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Unlike the mutations in this group, however, the C481S mutation in BTK is not a second mutation in a previously mutated gene, but rather a primary mutation in a gene that is not recurrently mutated in CLL, and it is mutated at the amino acid required for drug binding.”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In a recent preliminary study involving three patients with ibrutinib resistance, sequencing revealed the S707Y mutation in PLCγ2 that we identified in Patient 5 in our study but did not reveal BTK mutations.32”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [32] Burger JA, 2013, Blood source
plainn = 3- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“However, we recognize that our inability to identify small numbers of mutant clones in the presence of large numbers of nonmutant clones may mean that such variants were present but were not identified.”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This pattern of a mutation localized to the irreversible binding site of ibrutinib and the immediate downstream kinase is not commonly seen with reversible kinase inhibitors and may be a result of continuous (rather than intermittent) pressure on the drug target.”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Furthermore, many mutations discovered in PLCγ2 have been linked to the development of complex immune disorders as well as resistance to ibrutinib treatment in chronic lymphocytic leukaemia.”
From Characterisation of molecular mechanisms for PLCγ2 disease-linked variants (2024) · cites this paper as Woyach et al., 2014
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“whole-exome sequencing of six CLL patients with late relapses revealed C481S mutations in BTK of five patients and three distinct mutations in PLCG2 of two patients as follows: L845F, R665W, and S707Y in one patient with tumor cells also harboring a BTK C481S mutation and PLCG2 R665W representing the sole mutation in the other patient (29).”
From The Phospholipase Cγ2 Mutants R665W and L845F Identified in Ibrutinib-resistant Chronic Lymphocytic Leukemia Patients Are Hypersensitive to the Rho GTPase Rac2 Protein (2016) · cites this paper as [29]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“the R665W and L845F mutants of PLC␥ 2 appeared to be functionally normal in reconstituted DT40 chicken B cells in the absence of BCR stimulation, but to mediate moderately enhanced and markedly prolonged ibrutinib-resistant increases in [Ca 2ϩ ] i following BCR ligation with anti-IgM (29).”
From The Phospholipase Cγ2 Mutants R665W and L845F Identified in Ibrutinib-resistant Chronic Lymphocytic Leukemia Patients Are Hypersensitive to the Rho GTPase Rac2 Protein (2016) · cites this paper as [29]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Ibrutinib, acalabrutinib, and zanubrutinib bind covalently to residue C481 of BTK, and thus are susceptible to mutations changing C481 to another amino acid, most commonly C481S(19–21).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [19]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 [19]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The first reported BTK mutation in CLL patients with progressive disease on ibrutinib (19, 35)was a missense mutation changing C481 to serine (C481S)(19).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [19]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“PLCG2 S707Y, R665W, and L845F are gain-of-function missense mutations which prolong activation of BCR‐mediated downstream signaling, independent of BTK (19).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [19]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Specifically, genomic deletions (exon 19 or exons 20 through 22) or somatic mutations (R665W or S707Y) within the regulatory domain of PLCG2 constitutively activate PLCG2 and lead to BTK inhibitor resistance in leukemia patients 20,21 .”
From Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer’s disease (2023) · cites this paper as [21]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Mutations in the gene encoding phospholipase C-␥ 2 (PLC␥ 2 ) have been shown to be associated with resistance to targeted therapy of chronic lymphocytic leukemia (CLL) with the Bruton's tyrosine kinase inhibitor ibrutinib.”
The cited source says what the claim attributes to it.
In the citing paper
“The C481S mutation disrupts the covalent binding of ibrutinib to BTK and results in a weak and reversible interaction (affinity [KD], 0.2 nM vs. 10.4 nM) (19).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [19]
The cited source says what the claim attributes to it.
In the citing paper
“Mutations of PLCG have been observed to co-occur with BTK mutations in the same patient (12, 19, 24).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [19]
In the citing paper
“the resistance to ibrutinib emerges due to a cysteine to serine mutation (C418S) at the ibrutinib binding site in BTK [113, 114].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [114]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > DISCUSSION
“EGFR25,26 and ALK27 in lung cancer”
§ Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib > References
“27. Awad MM Katayama R McTigue M Acquired resistance to crizotinib from a mutation in CD74–ROS1 N Engl J Med 2013 368 2395 2401 23724914 PMC3878821”
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Metadata
- Authors
- Woyach, J. A., Furman, R. R., Liu, T.-M., Ozer, H. G., Zapatka, M., Ruppert, A. S., Xue, L., Li, D. H.-H., Steggerda, S. M., Versele, M., Dave, S. S., Zhang, J., Yilmaz, A. S., Jaglowski, S. M., Blum, K. A., Lozanski, A., Lozanski, G., James, D. F., Barrientos, J. C., Lichter, P., Stilgenbauer, S., Buggy, J. J., Chang, B. Y., Johnson, A. J., & Byrd, J. C.
- Affiliations
- German Cancer Research Center (DE)
- Weill Cornell Medicine (US)
- Pharmacyclics (United States) (US)
- Janssen (Belgium) (BE)
- Duke University (US)
- The Ohio State University (US)
- Northwell Health (US)
- Universität Ulm (DE)
- ORCID
- Woyach, Jennifer A.
- Furman, Richard R.
- Zapatka, Marc
- Ruppert, Amy S.
- Li, Daniel Hsieh-Hsin
- Versele, Matthias
- Zhang, Jenny
- Yilmaz, Ayse Selen
- Jaglowski, Samantha M.
- Blum, Kristie A.
- Lozanski, Gerard
- James, Danelle F.
- Barrientos, Jacqueline C.
- Lichter, Peter
- Stilgenbauer, Stephan
- Chang, Betty Y.
- Johnson, Amy J.
- Byrd, John C.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2014-06-12
- Volume
- 370
- Issue
- 24
- Pages
- 2286-2294
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4144824
- OpenAlex
- W2067064694
- Cited by
- 1,275
- References
- 34
- Citations by year
- 2026: 50 · 2025: 77 · 2024: 91 · 2023: 99 · 2022: 102 · 2021: 143 · 2020: 122 · 2019: 99 · 2018: 98 · 2017: 126 · 2016: 118 · 2015: 108 · 2014: 39
- FWCI
- 58.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Institutes of Health (4p01ca081534-16, 5k12ca133250-17, 2p30ca014236-51)
- National Cancer Institute (P30‐CA014236, R01CA183444, P01CA095426, K12‐CA133250, P50CA140158, K23 CA178183, R01CA177292, P30CA016058, P01-CA-081534)
- Topics
- Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- ibrutinib, Bruton's tyrosine kinase, chronic lymphocytic leukemia, drug resistance, B cell receptor signaling, irreversible kinase inhibitors, relapsed disease
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Adenine, Aged, Binding Sites, Humans, Middle Aged, Piperidines, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Receptors, Antigen, B-Cell, Recurrence, Leukemia, Lymphocytic, Chronic, B-Cell, Point Mutation, Sequence Analysis, DNA, Drug Resistance, Neoplasm, Phospholipase C gamma, Exome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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