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Title: Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia
Authors: Hart, S.
Goh, K.C.
Novotny-Diermayr, V.
Tan, Y.C.
Madan, B.
Amalini, C.
Ong, L.C.
Kheng, B.
Cheong, A.
Zhou, J. 
Chng, W.J.
Wood, J.M.
Keywords: AML
Issue Date: Nov-2011
Source: Hart, S., Goh, K.C., Novotny-Diermayr, V., Tan, Y.C., Madan, B., Amalini, C., Ong, L.C., Kheng, B., Cheong, A., Zhou, J., Chng, W.J., Wood, J.M. (2011-11). Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia. Blood Cancer Journal 1 (11) : -. ScholarBank@NUS Repository.
Abstract: FMS-like tyrosine kinase 3 (FLT3) is the most commonly mutated gene found in acute myeloid leukemia (AML) patients and its activating mutations have been proven to be a negative prognostic marker for clinical outcome. Pacritinib (SB1518) is a tyrosine kinase inhibitor (TKI) with equipotent activity against FLT3 (IC 50=22 nM) and Janus kinase 2 (JAK2, IC 50=23 nM). Pacritinib inhibits FLT3 phosphorylation and downstream STAT, MAPK and PI3K signaling in FLT3-internal-tandem duplication (ITD), FLT3-wt cells and primary AML blast cells. Oral administration of pacritinib in murine models of FLT3-ITDdriven AML led to significant inhibition of primary tumor growth and lung metastasis. Upregulation of JAK2 in FLT3-TKIresistant AML cells was identified as a potential mechanism of resistance to selective FLT3 inhibition. This resistance could be overcome by the combined FLT3 and JAK2 activities of pacritinib in this cellular model. Our findings provide a rationale for the clinical evaluation of pacritinib in AML including patients resistant to FLT3-TKI therapy. © 2011 Macmillan Publishers Limited All rights reserved.
Source Title: Blood Cancer Journal
ISSN: 20445385
DOI: 10.1038/bcj.2011.43
Appears in Collections:Staff Publications

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