Reference Detail

Ref Type

Journal Article

PMID

(22829080)

Authors

Hart S, Goh KC, Novotny-Diermayr V, Tan YC, Madan B, Amalini C, Ong LC, Kheng B, Cheong A, Zhou J, Chng WJ, Wood JM

Title

Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood cancer journal	1	11	2011 Nov	e44	Blood Cancer J

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Pacritinib	Pacritinib	18	9

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Pacritinib	Vonjo	SB1518\|SB-1518\|SB 1518	FLT3 Inhibitor 69 JAK2 Inhibitor - ATP competitive 15	Vonjo (pacritinib) is an inhibitor of JAK2 and FLT3, with activity against JAK2 V617F and FLT3 ITD, which potentially increases tumor cell apoptosis, induces cell cycle arrest, and decreases tumor growth (PMID: 22829080, PMID: 21691275). Vonjo (pacritinib) is FDA approved for use in patients with primary or secondary myelofibrosis (FDA.gov).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins	acute myeloid leukemia	predicted - sensitive	Pacritinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Vonjo (pacritinib) induced apoptosis and inhibited proliferation of acute myeloid leukemia cells harboring a FLT3-ITD mutation in culture, and inhibited tumor growth and induced tumor regression in cell line xenograft models (PMID: 22829080).	22829080