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1.
Leukemia ; 38(7): 1570-1580, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38454120

RESUMEN

Although Bruton's tyrosine kinase (BTK) inhibitors (BTKi) have significantly improved patient prognosis, mantle cell lymphoma (MCL) is still considered incurable due to primary and acquired resistance. We have recently shown that aberrant expression of the Src-family tyrosine kinase hematopoietic cell kinase (HCK) in MCL correlates with poor prognosis, and that genetic HCK perturbation impairs growth and integrin-mediated adhesion of MCL cells. Here, we show that KIN-8194, a dual inhibitor of BTK and HCK with in vivo activity against Myd88-L265P-driven diffuse large B-cell lymphoma and Waldenström Macroglobulinemia, has a potent growth inhibitory effect in MCL cell lines and primary MCL cells, irrespective of their sensitivity to BTKi (ibrutinib and acalabrutinib). In BTKi-resistant cells this is mediated by inhibition of HCK, which results in repression of AKT-S6 signaling. In addition, KIN-8194 inhibits integrin-mediated adhesion of BTKi-sensitive and insensitive MCL cells to fibronectin and stromal cells in an HCK-dependent manner. Finally, we show that MCL cells with acquired BTKi resistance retain their sensitivity to KIN-8194. Taken together, our data demonstrate that KIN-8194 inhibits growth and integrin-mediated adhesion of BTKi-sensitive MCL cells, as well as MCL cells with primary or acquired BTKi resistance. This renders KIN-8194 a promising novel treatment for MCL patients.


Asunto(s)
Agammaglobulinemia Tirosina Quinasa , Adhesión Celular , Proliferación Celular , Resistencia a Antineoplásicos , Integrinas , Linfoma de Células del Manto , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas c-hck , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/patología , Linfoma de Células del Manto/metabolismo , Linfoma de Células del Manto/genética , Humanos , Adhesión Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-hck/metabolismo , Proteínas Proto-Oncogénicas c-hck/genética , Proteínas Proto-Oncogénicas c-hck/antagonistas & inhibidores , Integrinas/metabolismo , Proliferación Celular/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Línea Celular Tumoral , Pirimidinas/farmacología , Adenina/análogos & derivados , Adenina/farmacología , Transducción de Señal/efectos de los fármacos
2.
Blood Cancer J ; 13(1): 37, 2023 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-36922488

RESUMEN

The paracaspase mucosa-associated lymphoid tissue 1 (MALT1) is a protease and scaffold protein essential in propagating B-cell receptor (BCR) signaling to NF-κB. The deubiquitinating enzyme cylindromatosis (CYLD) is a recently discovered MALT1 target that can negatively regulate NF-κB activation. Here, we show that low expression of CYLD is associated with inferior prognosis of diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) patients, and that chronic BCR signaling propagates MALT1-mediated cleavage and, consequently, inactivation and rapid proteasomal degradation of CYLD. Ectopic overexpression of WT CYLD or a MALT1-cleavage resistant mutant of CYLD reduced phosphorylation of IκBα, repressed transcription of canonical NF-κB target genes and impaired growth of BCR-dependent lymphoma cell lines. Furthermore, silencing of CYLD expression rendered BCR-dependent lymphoma cell lines less sensitive to inhibition of NF-κΒ signaling and cell proliferation by BCR pathway inhibitors, e.g., the BTK inhibitor ibrutinib, indicating that these effects are partially mediated by CYLD. Taken together, our findings identify an important role for MALT1-mediated CYLD cleavage in BCR signaling, NF-κB activation and cell proliferation, which provides novel insights into the underlying molecular mechanisms and clinical potential of inhibitors of MALT1 and ubiquitination enzymes as promising therapeutics for DLBCL, MCL and potentially other B-cell malignancies.


Asunto(s)
Enzima Desubiquitinante CYLD , Linfoma de Células B Grandes Difuso , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , FN-kappa B , Humanos , Caspasas/metabolismo , Enzima Desubiquitinante CYLD/genética , Enzima Desubiquitinante CYLD/metabolismo , Linfoma de Células B Grandes Difuso/patología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , FN-kappa B/metabolismo , Receptores de Antígenos de Linfocitos B , Transducción de Señal/fisiología
3.
Leukemia ; 35(3): 881-886, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32591642

RESUMEN

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma subtype arising from naïve B cells. Although novel therapeutics have improved patient prognosis, drug resistance remains a key problem. Here, we show that the SRC-family tyrosine kinase hematopoietic cell kinase (HCK), which is primarily expressed in the hematopoietic lineage but not in mature B cells, is aberrantly expressed in MCL, and that high expression of HCK is associated with inferior prognosis of MCL patients. HCK expression is controlled by the toll-like receptor (TLR) adaptor protein MYD88 and can be enhanced by TLR agonists in MCL cell lines and primary MCL. In line with this, primary MCL with high HCK expression are enriched for a TLR-signaling pathway gene set. Silencing of HCK expression results in cell cycle arrest and apoptosis. Furthermore, HCK controls integrin-mediated adhesion of MCL cells to extracellular matrix and stromal cells. Taken together, our data indicate that TLR/MYD88-controlled aberrant expression of HCK plays a critical role in MCL proliferation and survival as well as in retention of the malignant cells in the growth- and survival-supporting lymphoid organ microenvironment, thereby contributing to lymphomagenesis. These novel insights provide a strong rationale for therapeutic targeting of HCK in MCL.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Linfoma de Células del Manto/patología , Proteínas Proto-Oncogénicas c-hck/metabolismo , Microambiente Tumoral , Biomarcadores de Tumor/genética , Humanos , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/metabolismo , Pronóstico , Proteínas Proto-Oncogénicas c-hck/genética , Transducción de Señal
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