ArticleCell death & disease2022
Dual BTK/SYK inhibition with CG-806 (luxeptinib) disrupts B-cell receptor and Bcl-2 signaling networks in mantle cell lymphoma.
Article in Cell death & disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 23 citations in OpenAlex.
- Mechanisms of resistance to BTK inhibitors in B cell malignancies and emerging targeted strategies.Molecular therapy. Oncology · 2026Review
- Merging Micellar Catalysis and C-H Activation: Silver-Free Direct Arylation of Fluoroarenes in Water.ChemSusChem · 2026Article
- Cyclin-Dependent Kinase-9 and Oxidative Phosphorylation Inhibition Overcomes Ibrutinib Resistance in Mantle Cell Lymphoma.Cancer research communications · 2026Article
- Review
- Navigating the changing landscape of BTK-targeted therapies for B cell lymphomas and chronic lymphocytic leukaemia.Nature reviews. Clinical oncology · 2024Review
- Transcriptomic and proteomic differences in BTK-WT and BTK-mutated CLL and their changes during therapy with pirtobrutinib.Blood advances · 2024Article
- Biological and clinical determinants shaping heterogeneity in mantle cell lymphoma.Blood advances · 2024Review
- Application and progress of CRISPR/Cas9 gene editing in B-cell lymphoma: a narrative review.Translational cancer research · 2024Review
- B-cell receptor signaling activity identifies patients with mantle cell lymphoma at higher risk of progression.Scientific reports · 2024Article
- Unraveling the Role of the NLRP3 Inflammasome in Lymphoma: Implications in Pathogenesis and Therapeutic Strategies.International journal of molecular sciences · 2024Review
- BTK inhibition in primary central nervous system lymphoma: mechanisms, clinical efficacy, and future perspectives.Frontiers in oncology · 2024Review
- Beyond Bruton's tyrosine kinase inhibitors in mantle cell lymphoma: bispecific antibodies, antibody-drug conjugates, CAR T-cells, and novel agents.Journal of hematology & oncology · 2023Review
- Applying CRISPR-Cas9 screens to dissect hematological malignancies.Blood advances · 2023Review
- Generation of a humanized afucosylated BAFF-R antibody with broad activity against human B-cell malignancies.Blood advances · 2023Article
- Luxeptinib interferes with LYN-mediated activation of SYK and modulates BCR signaling in lymphoma.PloS one · 2023Article
- Review
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
Abstract
Aberrant B-cell receptor (BCR) signaling is a key driver in lymphoid malignancies. Bruton tyrosine kinase (BTK) inhibitors that disrupt BCR signaling have received regulatory approvals in therapy of mantle cell lymphoma (MCL). However, responses are incomplete and patients who experience BTK inhibitor therapy failure have dire outcomes. CG-806 (luxeptinib) is a dual BTK/SYK inhibitor in clinical development in hematologic malignancies. Here we investigated the pre-clinical activity of CG-806 in MCL. In vitro treatment with CG-806 thwarted survival of MCL cell lines and patient-derived MCL cells in a dose-dependent manner. CG-806 blocked BTK and SYK activation and abrogated BCR signaling. Contrary to ibrutinib, CG-806 downmodulated the anti-apoptotic proteins Mcl-1 and Bcl-xL, abrogated survival of ibrutinib-resistant MCL cell lines, and partially reversed the pro-survival effects of stromal microenvironment-mimicking conditions in primary MCL cells. Dual BTK/SYK inhibition led to mitochondrial membrane depolarization accompanied by mitophagy and metabolic reprogramming toward glycolysis. In vivo studies of CG-806 demonstrated improved survival in one of the two tested aggressive MCL PDX models. While suppression of the anti-apoptotic Bcl-2 family proteins and NFκB signaling correlated with in vivo drug sensitivity, OxPhos and MYC transcriptional programs were upregulated in the resistant model following treatment with CG-806. BAX and NFKBIA were implicated in susceptibility to CG-806 in a whole-genome CRISPR-Cas9 library screen (in a diffuse large B-cell lymphoma cell line). A high-throughput in vitro functional drug screen demonstrated synergy between CG-806 and Bcl-2 inhibitors. In sum, dual BTK/SYK inhibitor CG-806 disrupts BCR signaling and induces metabolic reprogramming and apoptosis in MCL. The Bcl-2 network is a key mediator of sensitivity to CG-806 and combined targeting of Bcl-2 demonstrates synergy with CG-806 warranting continued exploration in lymphoid malignancies.
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