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|Title:||Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia|
|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. https://doi.org/10.1038/bcj.2011.43|
|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|
|Appears in Collections:||Staff Publications|
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