Ibrutinib Resistance in Chronic Lymphocytic Leukemia

Furman, Richard R.; Cheng, Shuhua; Lü, Ping; Setty, Menu; Perez, Almudena Chaves; A, Guo; Racchumi, Joelle; Xu, Gang; Wu, Hao; Ma, Jiao; Steggerda, Susanne; Coleman, Morton; Leslie, Christina C.; Wang, Y. Lynn

doi:10.1056/nejmc1402716

Cited by 273 publications

(253 citation statements)

References 6 publications

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Section: Resistant Mutants Can Have a Selective Advantage In The Absesupporting

confidence: 82%

“…This finding is in agreement with the currently available data (14,15). Resistance mutations were detected when progressive disease was first observed, but not before treatment or during the initial response to treatment (including lymphocytosis) (14,15). In addition, the CLL cells found during lymphocytosis in nonprogressing patients have been found to be quiescent rather than carrying mutations that confer ibrutinib resistance (30,31).…”

Section: Resistant Mutants Can Have a Selective Advantage In The Absesupporting

confidence: 81%

“…The higher the number of mutational steps required, the less the chance of generating a resistant cell by the time of detection. Because the only documented ibrutinib-resistant mutants have been shown to be caused by point mutations, however, we will focus on this scenario (14,15).…”

Section: Btk Inhibitor-resistant Cll Cells Are Present Before the Stamentioning

confidence: 99%

“…In particular, drug-resistant mutants can arise that can initiate renewed growth. Indeed, in a minority of patients the growth of drug-resistant mutants has already been documented (13)(14)(15). Resistance has been found to be caused by point mutations, and a number of different mutants have been documented.…”

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confidence: 99%

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Evolution of ibrutinib resistance in chronic lymphocytic leukemia (CLL)

Komarova

Burger

Wodarz

2014

Proc. Natl. Acad. Sci. U.S.A.

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The Bruton tyrosine kinase inhibitor (BTKi) ibrutinib is a new targeted therapy for patients with chronic lymphocytic leukemia (CLL). Ibrutinib is given orally on a continuous schedule and induces durable remissions in the majority of CLL patients. However, a small proportion of patients initially responds to the BTKi and then develops resistance. Estimating the frequency, timing, and individual risk of developing resistance to ibrutinib, therefore, would be valuable for long-term management of patients. Computational evolutionary models, based on measured kinetic parameters of patients, allow us to approach these questions and to develop a roadmap for personalized prognosis and treatment management. Our kinetic models predict that BTKi-resistant mutants exist before initiation of ibrutinib therapy, although they only comprise a minority of the overall tumor burden. Furthermore, we can estimate the time required for resistant cells to grow to detectable levels. We predict that this can be highly variable, depending mostly on growth and death rates of the individual CLL cell clone. For a specific patient, this time can be predicted with a high degree of certainty. Our model can thus be used to predict for how long ibrutinib can suppress the disease in individual patients. Furthermore, the model can suggest whether prior debulking of the tumor with chemo-immunotherapy can prolong progression-free survival under ibrutinib. Finally, by applying the models to data that document progression during ibrutinib therapy, we estimated that resistant mutants might have a small (<2%) mean fitness advantage in the absence of treatment, compared with sensitive cells.evolutionary dynamics | drug resistance | personalized medicine | mathematical models | stochastic dynamics

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Section: Resistant Mutants Can Have a Selective Advantage In The Absesupporting

confidence: 82%

Section: Resistant Mutants Can Have a Selective Advantage In The Absesupporting

confidence: 81%

Section: Btk Inhibitor-resistant Cll Cells Are Present Before the Stamentioning

confidence: 99%

mentioning

confidence: 99%

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Evolution of ibrutinib resistance in chronic lymphocytic leukemia (CLL)

Komarova

Burger

Wodarz

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Pharmacologic inhibitors of Btk have demonstrated highly promising treatment effects for several nonHodgkin lymphomas and B-cell lymphomas 19,23 . However, the recent Btk inhibitor (Ibrutinib) acting on multiple B-cell-derived tumors was not exempted from resistance and side effects 24,25 . Therefore, developing a new treatment that targets Btk for treating B cell malignancies in patients with acquired resistance would be an important strategy.…”

Section: Introductionmentioning

confidence: 99%

PRIMA1 ile lösemi hücrelerinde Bruton tirozin kinaz inhibisyonu aracılığı apoptoz uyarımı

Mohammad

2017

Cukurova Medical Journal (Çukurova Üniversitesi Tıp Fakültesi Dergisi)

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AbstractÖz Purpose: Bruton's tyrosine kinase (Btk) is known to be critical for B-lymphocyte development, proliferation and differentiation of B-cell lineages, convey signal transduction through B cell receptor (BCR). The present study examined the anti-tumor effects of PRIMA-1 on Btk activity and explored the underlying mechanism, such as apoptosis. Materials and Methods:Western blot analysis and Quantitative real-time polymerase chain reaction were performed to check the effects of PRIMA-1 on Btk expression level in KBM3 and Namalwa cells. Wild-type Btk and Btk-NLS (nuclear targeted Btk) expression plasmids were transfected in COS-7 cells to establish and characterize the role of Btk in apoptosis using fluorescent microscopy and FACS assay. Results: İn this study, we observed that exposure of acute myelomonocytic leukemia cells to anti-leukemic drug (PRIMA-1) suppressed Btk expression at mRNA and protein level. Consequently, we also noticed a reduction in the expression of Nrf2 and HO-1 proteins. Remarkably, Btk nuclear localization was increased in response to low PRIMA-1 exposure, while higher concentrations of PRIMA-1 suppressed Btk expression. Furthermore, overexpression of nuclear targeted decreased apoptosis and increased cell viability compared to the wild-type Btk. Conclusion: Our findings suggest that nuclear Btk reduces the cell apoptosis in response to PRIMA-1 exposure through oxidative response via Nrf2 and HO-1.

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Ibrutinib, a Carboxylic Acid Amide Inhibitor of Bruton's Tyrosine Kinase

Owens

2016

Bioactive Carboxylic Compound Classes: Pharmaceuticals and Agrochemicals

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Ibrutinib Resistance in Chronic Lymphocytic Leukemia

Cited by 273 publications

References 6 publications

Evolution of ibrutinib resistance in chronic lymphocytic leukemia (CLL)

Evolution of ibrutinib resistance in chronic lymphocytic leukemia (CLL)

PRIMA1 ile lösemi hücrelerinde Bruton tirozin kinaz inhibisyonu aracılığı apoptoz uyarımı

Ibrutinib, a Carboxylic Acid Amide Inhibitor of Bruton's Tyrosine Kinase

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