Utilizad este identificador para citar o enlazar este documento: http://hdl.handle.net/2072/376578

Título:	Activity of the novel BCR kinase inhibitor IQS019 in preclinical models of B-cell non-Hodgkin lymphoma
Autor/a:	Borrell Bilbao, José Ignacio; Teixidó i Closa, Jordi; Puig de la Bellacasa Cazorla, 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.
Otros autores:	Universitat Ramon Llull. IQS
Abstract:	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.
Fecha de creación:	03-2017
Materias (CDU):	616 - Patologia. Medicina clínica. Oncologia
Materia(s):	Cèl·lules--Migració Cèl·lules B Limfomes B-NHL Btk Lyn Syk Cell migration Mouse model
Derechos:	L'accés als continguts d'aquest document queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons:http://creativecommons.org/licenses/by/4.0/ © L'autor/a
Páginas:	14 p.
Tipo de documento:	Artículo Artículo - Versión publicada
DOI:	https://doi.org/10.1186/s13045-017-0447-6
Editor:	BioMed Central
Publish at:	Journal of Hematology & Oncology. Vol.10, n.80 (2017)
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