ArticleOncotarget2017
Dual SYK/JAK inhibition overcomes ibrutinib resistance in chronic lymphocytic leukemia: Cerdulatinib, but not ibrutinib, induces apoptosis of tumor cells protected by the microenvironment.
Article in Oncotarget, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
30 citing papers in PubMed, 51 citations in OpenAlex.
- Identification of a genetic signature enriching for response to ibrutinib in relapsed/refractory follicular lymphoma in the DAWN phase 2 trial.Cancer medicine · 2022Trial
- Mechanisms of resistance to BTK inhibitors in B cell malignancies and emerging targeted strategies.Molecular therapy. Oncology · 2026Review
- Palladium-catalyzed Suzuki-Miyaura and Buchwald-Hartwig cross-coupling reactions towards the synthesis of pharmacologically potent pyrimidine-based molecules.Molecular diversity · 2026Review
- Review
- B cell receptor signaling and associated pathways in the pathogenesis of chronic lymphocytic leukemia.Frontiers in oncology · 2024Review
- Development of SYK NanoBRET cellular target engagement assays for gain-of-function variants.Frontiers in chemical biology · 2024Article
- Novel Therapeutic Strategies in the Topical Treatment of Atopic Dermatitis.Pharmaceutics · 2022Review
- Targeting the immune microenvironment in mantle cell lymphoma: implications for current and emerging therapies.Leukemia & lymphoma · 2022Review
- Review
- Atopic dermatitis: an expanding therapeutic pipeline for a complex disease.Nature reviews. Drug discovery · 2022Review
- Bruton's tyrosine kinase inhibitors in the treatment of primary central nervous system lymphoma: A mini-review.Frontiers in oncology · 2022Review
- Targeted and cellular therapies in lymphoma: Mechanisms of escape and innovative strategies.Frontiers in oncology · 2022Review
- Schlafen 11 expression in human acute leukemia cells with gain-of-function mutations in the interferon-JAK signaling pathway.iScience · 2021Article
- Second-Generation Jak2 Inhibitors for Advanced Prostate Cancer: Are We Ready for Clinical Development?Cancers · 2021Review
- Review
- Bruton's Tyrosine Kinase Inhibition as an Emerging Therapy in Systemic Autoimmune Disease.Drugs · 2021Review
- Novel Agents in Chronic Lymphocytic Leukemia: New Combination Therapies and Strategies to Overcome Resistance.Cancers · 2021Review
- Ibrutinib and venetoclax target distinct subpopulations of CLL cells: implication for residual disease eradication.Blood cancer journal · 2021Article
- Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancies.Frontiers in oncology · 2020Article
- Antitumor Activity and Mechanism of Robustic Acid fromMolecules (Basel, Switzerland) · 2020Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Ibrutinib (BTK inhibitor) has generated remarkable responses in CLL. However, the drug, to a large extent, does not cause cell death directly and does not eradicate CLL malignant clones. Inability to eradicate CLL has fostered resistance generation. Once patients become resistant, they do poorly with a median survival of 3-4 months. Novel therapeutic strategies are needed to prevent resistance, improve treatment outcome and ultimately cure the disease. Herein, we explore dual targeting of the BCR and JAK-STAT pathways with a novel single agent, cerdulatinib, which selectively inhibits both SYK (a BCR component) and JAK kinases. We demonstrated that cerdulatinib delivered potent tumor inhibition in 60 primary CLL patient samples, especially in those with poor prognostic indicators. Importantly, cerdulatinib, but not ibrutinib, is able to overcome the support of microenvironment and induces CLL cell death at clinically achievable concentrations. Notably, cerdulatinib blocked proliferation of ibrutinib-resistant primary CLL cells and of BTKC481S-transfected/ibrutinib-resistant lymphoma cells. These anti-tumor effects are well correlated with the inhibition of BCR and JAK-STAT signaling and downstream inhibition of the functions of AKT, ERK and NFκB. Collectively, our results show that simultaneous targeting of BCR and JAK-STAT pathways is a more effective strategy relative to single BTK inhibition.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.