title: Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia.
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 n) and Janus kinase 2 (JAK2, IC(50)=23 n). Pacritinib inhibits FLT3 phosphorylation and downstream STAT, MAPK and PI3 K signaling in FLT3-internal-tandem duplication (ITD), FLT3-wt cells and primary AML blast cells. Oral administration of pacritinib in murine models of FLT3-ITD-driven AML led to significant inhibition of primary tumor growth and lung metastasis. Upregulation of JAK2 in FLT3-TKI-resistant 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.
authors: S
authors: S
authors: Hart
authors: K C
authors: KC
authors: Goh
authors: V
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authors: Novotny-Diermayr
authors: Y C
authors: YC
authors: Tan
authors: B
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authors: Madan
authors: C
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authors: Amalini
authors: L C
authors: LC
authors: Ong
authors: B
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authors: Kheng
authors: A
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authors: Cheong
authors: J
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authors: Zhou
authors: W J
authors: WJ
authors: Chng
authors: J M
authors: JM
authors: Wood