Targeting the Spleen Tyrosine Kinase with Fostamatinib as a Strategy against Waldenström Macroglobulinemia

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Isere KuiatseRobert Z Orlowski

Abstract

Waldenström macroglobulinemia (WMG) is a lymphoproliferative disorder characterized by good initial responses to standard therapeutics, but only a minority of patients achieve complete remissions, and most inevitably relapse, indicating a need for novel agents. B-cell receptor signaling has been linked to clonal evolution in WMG, and Spleen tyrosine kinase (Syk) is overexpressed in primary cells, suggesting that it could be a novel and rational target. We studied the impact of the Syk inhibitor fostamatinib on BCWM.1 and MWCL-1 WMG-derived cell lines both in vitro and in vivo, as well as on primary patient cells. In WMG-derived cell lines, fostamatinib induced a time- and dose-dependent reduction in viability, associated with activation of apoptosis. At the molecular level, fostamatinib reduced activation of Syk and Bruton's tyrosine kinase, and also downstream signaling through MAPK kinase (MEK), p44/42 MAPK, and protein kinase B/Akt. As a single agent, fostamatinib induced tumor growth delay in an in vivo model of WMG, and reduced viability of primary WMG cells, along with inhibition of p44/42 MAPK signaling. Finally, fostamatinib in combination with other agents, including dexamethasone, bortezomib, and rituximab, showed enh...Continue Reading

References

May 16, 1998·The Journal of Biological Chemistry·M DeckertY C Liu
Mar 14, 2007·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Christine I ChenUNKNOWN National Cancer Institute of Canada Clinical Trials Group
Jun 5, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Steven P TreonAshraf Badros
Mar 13, 2008·Blood·Xavier LeleuIrene M Ghobrial
Feb 10, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Irene M GhobrialThomas E Witzig
Dec 30, 2010·The Journal of Biological Chemistry·Chad C BjorklundRobert Z Orlowski
Jan 18, 2011·Hematology·Thomas E Witzig, Mamta Gupta
Mar 29, 2011·Expert Opinion on Investigational Drugs·Dimitar G Efremov, Luca Laurenti
Apr 22, 2011·American Journal of Hematology·Efstathios KastritisMeletios A Dimopoulos
Aug 31, 2012·The New England Journal of Medicine·Steven P TreonZachary R Hunter
Mar 26, 2013·Current Opinion in Pharmacology·David L Simmons
Jul 26, 2013·Nature Reviews. Immunology·Robert C Rickert
Oct 12, 2013·British Journal of Haematology·Amin Aalipour, Ranjana H Advani
Jan 11, 2014·Expert Review of Hematology·Ilyas SahinIrene M Ghobrial

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Citations

Apr 5, 2016·Oncogene·E MandatoF Piazza
Nov 9, 2016·Best Practice & Research. Clinical Haematology·Aneel PaulusAsher Chanan-Khan
Nov 9, 2016·Best Practice & Research. Clinical Haematology·Sikander AilawadhiAsher Chanan-Khan
Jul 8, 2020·Expert Review of Anticancer Therapy·Maria GavriatopoulouMeletios Athanasios Dimopoulos
Sep 22, 2020·Expert Opinion on Emerging Drugs·Fotiou DespinaKastritis Efstathios
Mar 25, 2017·Molecular Cancer Therapeutics·Stuart W EmberErnst Schönbrunn
Jun 18, 2021·Expert Opinion on Drug Safety·Magdalini MigkouMeletios Athanasios Dimopoulos
Aug 8, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Essam EzzeldinRashad Alsalahi

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