Second-generation inhibitors of Bruton tyrosine kinase

Wu, Jingjing; Liu, Christina; Tsui, Stella T.; Liu, Delong

doi:10.1186/s13045-016-0313-y

Cited by 171 publications

(150 citation statements)

References 88 publications

(100 reference statements)

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“…Clinical trials are currently evaluating second-generation BTK inhibitors (for example, acalabrutinib 148 , ONO/GS-4059 (REF. 149) or BGB-3111) to determine whether any one of these drugs has a superior therapeutic index than that of ibrutinib 150 .…”

Section: Managementmentioning

confidence: 99%

Chronic lymphocytic leukaemia

Kipps

Stevenson

et al. 2017

Nat Rev Dis Primers

397

404

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Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5+ B cells that is characterized by the accumulation of small, mature-appearing lymphocytes in the blood, marrow and lymphoid tissues. Signalling via surface immunoglobulin, which constitutes the major part of the B cell receptor, and several genetic alterations play a part in CLL pathogenesis, in addition to interactions between CLL cells and other cell types, such as stromal cells, T cells and nurse-like cells in the lymph nodes. The clinical progression of CLL is heterogeneous and ranges from patients who require treatment soon after diagnosis to others who do not require therapy for many years, if at all. Several factors, including the immunoglobulin heavy-chain variable region gene (IGHV) mutational status, genomic changes, patient age and the presence of comorbidities, should be considered when defining the optimal management strategies, which include chemotherapy, chemoimmunotherapy and/or drugs targeting B cell receptor signalling or inhibitors of apoptosis, such as BCL-2. Research on the biology of CLL has profoundly enhanced our ability to identify patients who are at higher risk for disease progression and our capacity to treat patients with drugs that selectively target distinctive phenotypic or physiological features of CLL. How these and other advances have shaped our current understanding and treatment of patients with CLL is the subject of this Primer.

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Section: Managementmentioning

confidence: 99%

Chronic lymphocytic leukaemia

Kipps

Stevenson

et al. 2017

Nat Rev Dis Primers

397

404

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“…A first generation irreversible BTK inhibitor Imbruvica (Ibrutinib) is FDA-approved for treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström macroglobulinemia (Table 1) [75, 76]. As Imbruvica inhibits multiple Tec kinases that are important in other immune cell types, more potent and selective second generation BTK inhibitors, such as Acalabrutinib, have been developed and are now showing promise in Phase I and II clinical trials (Table 1) [77••, 78]. A PI3Kδ inhibitor, Zydelig (Idelalisib), has also been FDA-approved for the treatment of relapsed CLL, follicular B cell non-Hodgkin lymphoma (FL) and small lymphocytic lymphoma (SLL), again underscoring the critical role played by PI3K in B cells [79, 80].…”

Section: Activation Of Non-receptor Tyrosine Kinase Signaling: Tec Famentioning

confidence: 99%

PI3K signaling in cancer: beyond AKT

Lien

Dibble

Toker

2017

Current Opinion in Cell Biology

366

253

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The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most frequently altered pathways in human cancer and has a critical role in driving tumor initiation and progression. Although PI3K and its lipid product phosphatidylinositol-3,4,5-trisphosphate (PIP3) have been shown to activate multiple downstream signaling proteins, the vast majority of studies have focused on the protein kinase AKT as the dominant effector of PI3K signaling. However, recent studies have demonstrated many contexts under which other PIP3-dependent signaling proteins critically contribute to cancer progression, illustrating the importance of understanding AKT-independent signaling downstream of PI3K. Here, we highlight three PI3K-dependent, but AKT-independent, signaling branches that have recently been shown to have important roles in promoting phenotypes associated with malignancy. First, the PDK1 -mTORC2-SGK axis can substitute for AKT in survival, migration, and growth signaling and has emerged as a major mechanism of resistance to PI3K and AKT inhibitors. Second, Rac signaling mediates the reorganization of the actin cytoskeleton to regulate cancer cell migration, invasion, and metabolism. Finally, the TEC family kinase BTK has a critical role in B cell function and malignancy and represents a recent example of an effective therapeutic target in cancer. These mechanisms highlight how understanding PI3K-dependent, but AKT-independent, signaling mechanisms that drive cancer progression will be crucial for the development of novel and more effective approaches for targeting the PI3K pathway for therapeutic benefit in cancer.

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“…While the second generation BTK inhibitors, including acalabrutinib (ACP-196), tirabrutinib (GS-4059, ONO-4059), spebrutinib (CC-292), and BGB-3111, are all irreversible inhibitors that bind BTK C481 and are therefore not reported to have efficacy against the BTK C481S mutation [52], some drugs earlier in development do inhibit BTK C481S. The drug ARQ 531 is an ATP competitive inhibitor of BTK that blocks BCR signaling in vitro, even in primary patient samples possessing BTK C481S mutations [53].…”

Section: Characteristics Of Mutations That Are Sufficient For Acquirementioning

confidence: 99%

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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Second-generation inhibitors of Bruton tyrosine kinase

Cited by 171 publications

References 88 publications

Chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia

PI3K signaling in cancer: beyond AKT

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

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