Activity of the novel BCR kinase inhibitor IQS019 in preclinical models of B-cell non-Hodgkin lymphoma

Background Pharmacological inhibition of B cell receptor (BCR) signaling has recently emerged as an effective approach in a wide range of B lymphoid neoplasms. However, despite promising clinical activity of the first Bruton’s kinase (Btk) and spleen tyrosine kinase (Syk) inhibitors, a small fractio...

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Detalles Bibliográficos
Autores: Borrell, Jose I., Teixidó, Jordi, Puig de la Bellacasa, Raimon, Roué, Gaël, Balsas, P., Esteve-Arenys, A., Roldán, J., Jiménez, L., Rodríguez, V., Valero, J. G., Chamorro-Jorganes, A., Matas-Céspedes, A., Moros, A., Martínez, A., Campo, E., Sáez-Borderías, A., Pérez-Galán, P., Colomer, D.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:España
Institución:Universitat Ramon Llull (URL)
Repositorio:DAU Arxiu Digital de la Universitat Ramon Llull
OAI Identifier:oai:dau.url.edu:20.500.14342/1004
Acceso en línea:http://hdl.handle.net/20.500.14342/1004
https://doi.org/10.1186/s13045-017-0447-6
Access Level:acceso abierto
Palabra clave:Cèl·lules--Migració
Cèl·lules B
Limfomes
B-NHL
Btk
Lyn
Syk
Cell migration
Mouse model
616
Descripción
Sumario:Background Pharmacological inhibition of B cell receptor (BCR) signaling has recently emerged as an effective approach in a wide range of B lymphoid neoplasms. However, despite promising clinical activity of the first Bruton’s kinase (Btk) and spleen tyrosine kinase (Syk) inhibitors, a small fraction of patients tend to develop progressive disease after initial response to these agents. Methods We evaluated the antitumor activity of IQS019, a new BCR kinase inhibitor with increased affinity for Btk, Syk, and Lck/Yes novel tyrosine kinase (Lyn), in a set of 34 B lymphoid cell lines and primary cultures, including samples with acquired resistance to the first-in-class Btk inhibitor ibrutinib. Safety and efficacy of the compound were then evaluated in two xenograft mouse models of B cell lymphoma. Results IQS019 simultaneously engaged a rapid and dose-dependent de-phosphorylation of both constitutive and IgM-activated Syk, Lyn, and Btk, leading to impaired cell proliferation, reduced CXCL12-dependent cell migration, and induction of caspase-dependent apoptosis. Accordingly, B cell lymphoma-bearing mice receiving IQS019 presented a reduced tumor outgrowth characterized by a decreased mitotic index and a lower infiltration of malignant cells in the spleen, in tight correlation with downregulation of phospho-Syk, phospho-Lyn, and phospho-Btk. More interestingly, IQS019 showed improved efficacy in vitro and in vivo when compared to the first-in-class Btk inhibitor ibrutinib, and was active in cells with acquired resistance to this latest. Conclusions These results define IQS019 as a potential drug candidate for a variety of B lymphoid neoplasms, including cases with acquired resistance to current BCR-targeting therapies.

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