TY - JOUR
T1 - Activity of the novel BCR kinase inhibitor IQS019 in preclinical models of B-cell non-Hodgkin lymphoma
AU - Balsas, P.
AU - Esteve-Arenys, A.
AU - Roldán, J.
AU - Jiménez, L.
AU - Rodríguez, V.
AU - Valero, J. G.
AU - Chamorro-Jorganes, A.
AU - De La Bellacasa, R. Puig
AU - Teixidó, J.
AU - Matas-Céspedes, A.
AU - Moros, A.
AU - Martínez, A.
AU - Campo, E.
AU - Sáez-Borderías, A.
AU - Borrell, J. I.
AU - Pérez-Galán, P.
AU - Colomer, D.
AU - Roué, G.
N1 - Funding Information:
This work was financially supported by Fondo de Investigación Sanitaria PI12/01847 and PI15/00102 (to G.R.), PI0110094 (to A.M.), European Regional Development Fund (ERDF) “Una manera de hacer Europa”, Ministerio de Ciencia e Innovación, SAF12/31242 (to D.C.), SAF11/29326 (to P.P.-G.), SAF2010-C21617-C02 (to JI.B.), Redes Temáticas de Investigación Cooperativa de Cáncer from the Instituto de Salud Carlos III (ISCIII) RD12/ 0036/0004 (to D.C.) and RD12/0036/0039 (to E.C.) and Generalitat de Catalunya 2014SGR346 (to D.C.) and 2014SGR795 (to E.C.). A.E.-A. and A.M.-C. were recipients of predoctoral fellowships from Ministerio de Ciencia e Innovación and A.M. hold an IDIBAPS intramural predoctoral fellowship. R.P. was supported by a grant within the Talent empresa 2009 program (2009 TEM 00128) of the Generalitat de Catalunya. AC-J holds a postdoctoral fellowship from Catalonian Agency for Management of University and Research Grants (AGAUR, Beatriu de Pinos program). This work was carried out at the Esther Koplowitz Center, Barcelona, under the CERCA Program (Generalitat de Catalunya).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/3/31
Y1 - 2017/3/31
N2 - 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.
AB - 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.
KW - B-NHL
KW - Btk
KW - Cell migration
KW - Lyn
KW - Mouse model
KW - Syk
UR - http://www.scopus.com/inward/record.url?scp=85016500943&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=pure_univeritat_ramon_llull&SrcAuth=WosAPI&KeyUT=WOS:000397814200001&DestLinkType=FullRecord&DestApp=WOS_CPL
U2 - 10.1186/s13045-017-0447-6
DO - 10.1186/s13045-017-0447-6
M3 - Article
C2 - 28359287
AN - SCOPUS:85016500943
SN - 1756-8722
VL - 10
JO - Journal of Hematology and Oncology
JF - Journal of Hematology and Oncology
IS - 1
M1 - 80
ER -