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 (IC50=22 n) and Janus kinase 2 (JAK2, IC50=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.
Highlights
Acute myeloid leukemia (AML) is characterized by aberrant proliferation of myeloid progenitor cells that have lost the ability to differentiate into mature cells
To investigate whether its enzyme inhibitory properties translate into modulation of FMS-like tyrosine kinase 3 (FLT3) signaling pathways in the cellular context, the effects of pacritinib on FLT3 autophosphorylation and downstream STAT5 phosphorylation, pERK1/2 (T202,Y204) and pAkt (T308) were investigated in two FLT3-internal-tandem duplications (ITDs)-harboring cell lines (MV4-11 and MOLM-13) and one FLT3-wt-bearing cell line (RS4;11)
FLT3-ITD harboring MV4-11 cells were treated for 3 h with different concentrations of pacritinib and pFLT3, pSTAT5 and
Summary
Acute myeloid leukemia (AML) is characterized by aberrant proliferation of myeloid progenitor cells that have lost the ability to differentiate into mature cells. Treatment of the AML blast cells with pacritinib for 3 h led to a dose-dependent decrease of pFLT3, pSTAT3 and pSTAT5 with an IC50 below 0.5 mM (Figure 4a).
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