PLCG2 C2 domain mutations co-occur with BTK and PLCG2 resistance mutations in chronic lymphocytic leukemia undergoing ibrutinib treatment

Jones, Daniel; Woyach, Jennifer A.; Zhao, Weiqiang; Caruthers, Sean; Tu, Huolin; Coleman, Joshua F.; Byrd, John C.; Johnson, Amy J.; Lozanski, Gerard

doi:10.1038/leu.2017.110

Cited by 60 publications

(70 citation statements)

References 15 publications

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“…To our knowledge, the current study is the first to report BTK mutations in patients with CLL who were treated with acalabrutinib (a second‐generation selective BTK inhibitor that is more potent than ibrutinib). Last, the results of the current study independently confirm that BTK mutations contribute to ibrutinib resistance in at least a subset of patients, consistent with previously reported findings …”

Section: Discussionsupporting

confidence: 92%

Targeted multigene deep sequencing of Bruton tyrosine kinase inhibitor–resistant chronic lymphocytic leukemia with disease progression and Richter transformation

Kanagal‐Shamanna

Jain

Patel

et al. 2018

Cancer

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Background In a proportion of patients with chronic lymphocytic leukemia (CLL), resistance to Bruton tyrosine kinase (BTK) inhibitors (BTKi) is attributed to acquired BTK/phospholipase C gamma 2 (PLCG2) mutations. However, knowledge regarding additional genetic lesions associated with BTK/PLCG2 mutations, and gene mutations in patients lacking BTK/PLCG2 mutations, is limited. Methods Using targeted deep sequencing, mutations in 29 genes associated with CLL and/or the BCR signaling pathway were assessed in patients with CLL who developed resistance to BTK inhibition with ibrutinib/acalabrutinib at a single institution. Results The study group included 29 patients with BTKi‐resistant CLL, 23 patients with disease progression, and 6 patients with Richter transformation (RT). The median times to disease progression and RT were 33.3 months and 13.3 months, respectively. In 11 patients, sequencing was possible at both baseline (prior to treatment with BTKi) and at time of disease progression/RT. Of these patients, 4 demonstrated BTK mutations at the time of disease progression/RT; patients without BTK mutations frequently acquired mutations associated with disease progression/RT in TP53, SF3B1, and CARD11, whereas additional mutations were rare in patients with BTK‐mutated CLL. Sequencing of all 29 patients at the time of disease progression/RT identified BTK mutations at a frequency of 66%, including a novel V537I mutation. Among patients with disease progression, BTK mutations were observed in 16 patients (70%). The median time to disease progression was shorter in patients without BTK mutations compared with those with BTK‐mutated CLL. Among patients with RT, SF3B1 mutations were more frequent than BTK mutations (67% vs 50%). Following BTKi discontinuation, we sequential mutation analysis was performed in 2 patients with RT and 3 patients with disease progression in the setting of persistent disease. Both patients with RT demonstrated disappearance of BTK and expansion of TP53 mutations. All 3 patients with disease progression received venetoclax and demonstrated suppression of BTK mutations. Conclusions Longitudinal, targeted, multigene deep sequencing is informative for the clinical monitoring of mutational evolution in patients with CLL who are receiving BTKi.

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Section: Discussionsupporting

confidence: 92%

Targeted multigene deep sequencing of Bruton tyrosine kinase inhibitor–resistant chronic lymphocytic leukemia with disease progression and Richter transformation

Kanagal‐Shamanna

Jain

Patel

et al. 2018

Cancer

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“…We also provide evidence that early and sensitive detection of BTK mutations may be predictive of an impending relapse. After the initial discovery of the canonical BTK and PLCG2 mutations underlying ibrutinib resistance by whole exome sequencing studies, additional mutations were described in various domains of these two genes, predominantly detected in single patients with low VAFs . As in many of the initial studies, only mutation hotspots were analyzed or NGS studies were performed with a relatively low sequencing depth, the clonal complexity of ibrutinib resistance in the context of BTK and PLCG2 mutations may well have been underestimated.…”

Section: Discussionmentioning

confidence: 99%

Dissection of subclonal evolution by temporal mutation profiling in chronic lymphocytic leukemia patients treated with ibrutinib

Gángó

Alpár

Gálik

et al. 2019

Intl Journal of Cancer

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The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is inducing durable responses in chronic lymphocytic leukemia (CLL) patients with refractory/relapsed disease or with TP53 defect, with BTK and phospholipase C gamma 2 (PLCG2) mutations representing the predominant mechanisms conferring secondary ibrutinib resistance. To understand the landscape of genomic changes and the dynamics of subclonal architecture associated with ibrutinib treatment, an ultra‐deep next‐generation sequencing analysis of 30 recurrently mutated genes was performed on sequential samples of 20 patients, collected before and during single‐agent ibrutinib treatment. Mutations in the SF3B1, MGAand BIRC3 genes were enriched during ibrutinib treatment, while aberrations in the BTK, PLCG2, RIPK1, NFKBIE and XPO1 genes were exclusively detected in posttreatment samples. Besides the canonical mutations, four novel BTK mutations and three previously unreported PLCG2 variants were identified. BTK and PLCG2 mutations were backtracked in five patients using digital droplet PCR and were detectable on average 10.5 months before clinical relapse. With a median follow‐up time of 36.5 months, 7/9 patients harboring BTK mutations showed disease progression based on clinical and/or laboratory features. In conclusion, subclonal heterogeneity, dynamic clonal selection and various patterns of clonal variegation were identified with novel resistance‐associated BTK mutations in individual patients treated with ibrutinib.

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“…Nearly all reported BTK mutations in the dozens of cases reported in the literature have occurred at the cysteine 481 hotspot [5, 8, 10], except for a few additional cases reported with mutations at T316, T474, and L528 [6, 11, 34]. While the reported PLCG2 mutations are more varied, and involve amino acid residues P664, R665, S707, L845, D993, D1140, and M1141 [5, 7, 10], they seem to cluster within particular domains [35], rather than being randomly distributed throughout the protein. These BTK/PLCG2 mutations are not the only recurrent genetic events seen in ibrutinib-resistant patients.…”

Section: Characteristics Of Mutations That Are Sufficient For Acquirementioning

confidence: 99%

“…These mutants are also hyper-responsive to upstream agonist signals, such as those provide by the GTPase Rac2 [43]. However, over a dozen different mutations in PLCG2 have been described, many lying outside of the SH2 domain, and the effect of many of these mutations on protein function are unclear (Table 2) [35]. For example, the C2 domain of PLCG2 mediates interactions with membrane phospholipids in a calcium-dependent fashion.…”

Section: Characteristics Of Mutations That Are Sufficient For Acquirementioning

confidence: 99%

“…Mutations in a conserved hotspot (amino acids 1140–1144) within this domain may alter its electrostatic properties and facilitate membrane interactions that otherwise would not occur. However, these mutations almost exclusively occur in the setting of other BTK or PLCG2 mutations, possibly within the same cell [35], raising the question of whether they can independently activate the pathway or whether their role is more complex [35]. In sum, PLCG2 mutations, at least those within the inhibitory SH2 domain, represent a method of sustaining signaling through the BCR pathway even in the presence of ibrutinib, and in vitro are drug-resistant mutants.…”

Section: Characteristics Of Mutations That Are Sufficient For Acquirementioning

confidence: 99%

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AreBTKandPLCG2mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia?

Lampson

Brown

2018

Expert Review of Hematology

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Introduction: Ibrutinib is the first BTK inhibitor to show efficacy in chronic lymphocytic leukemia (CLL) and is also the first BTK inhibitor to which patients have developed resistance. Mutations in BTK and PLCG2 are found in ≈80% of CLL patients with acquired resistance to ibrutinib, but it remains unclear if these mutations are merely associated with disease relapse or directly cause it. Areas covered: Unique properties of both CLL and ibrutinib that complicate attempts to definitively conclude whether BTK/PLCG2 mutations are passengers or drivers of ibrutinib-resistant disease are reviewed. Characteristics of mutations that drive drug resistance are summarized and whether BTK/PLCG2 mutations possess these is discussed. These characteristics include (1) identification in multiple patients with acquired resistance, (2) in vitro validation of drug-resistant properties, (3) mutual exclusivity with one another, (4) increasing frequency over time on drug, and (5) high frequency at the time and site of clinical relapse. Expert Commentary: While BTK/PLCG2 mutations have characteristics suggesting that they can drive ibrutinib resistance, this conclusion remains formally unproven until specific inhibition of such mutations is shown to cause regression of ibrutinib-resistant CLL. Data suggest that alternative mechanisms of resistance do exist in some patients.

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PLCG2 C2 domain mutations co-occur with BTK and PLCG2 resistance mutations in chronic lymphocytic leukemia undergoing ibrutinib treatment

Cited by 60 publications

References 15 publications

Targeted multigene deep sequencing of Bruton tyrosine kinase inhibitor–resistant chronic lymphocytic leukemia with disease progression and Richter transformation

Targeted multigene deep sequencing of Bruton tyrosine kinase inhibitor–resistant chronic lymphocytic leukemia with disease progression and Richter transformation

Dissection of subclonal evolution by temporal mutation profiling in chronic lymphocytic leukemia patients treated with ibrutinib

AreBTKandPLCG2mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia?

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