Williams AB, Li L, Nguyen B, Brown P, Levis M, Small DFluvastatin inhibits FLT3 glycosylation in human and murine cells and prolongs survival of mice with FLT3/ITD leukemia. Blood 120: 3069-3079

Departments of Oncology and.
Blood (Impact Factor: 10.45). 08/2012; 120(15):3069-79. DOI: 10.1182/blood-2012-01-403493
Source: PubMed


FLT3 is frequently mutated in acute myeloid leukemia (AML), but resistance has limited the benefit of tyrosine kinase inhibitors (TKI). We demonstrate that statins can impair FLT3 glycosylation, thus leading to loss of surface expression and induction of cell death, as well as mitigation of TKI resistance. Immunofluorescence microscopy confirms a reduction in surface localization and an increase in intracellular FLT3/internal tandem duplication (ITD) accumulation. This aberrant localization was associated with increased STAT5 activation but inhibition of both MAPK and AKT phosphorylation. Growth inhibition studies indicate that FLT3/ITD-expressing cells were killed with an IC(50) within a range of 0.2-2μM fluvastatin. Several mechanisms of resistance could be circumvented by fluvastatin treatment. An increase in the IC(50) for inhibition of phosphorylated FLT3/ITD by lestaurtinib caused by exogenous FLT3 ligand, resistance to sorafenib caused by the D835Y or FLT3/ITD N676K mutations, and activation of the IL-3 compensatory pathway were all negated by fluvastatin treatment. Finally, fluvastatin treatment in vivo reduced engraftment of BaF3 FLT3/ITD cells in Balb/c mice. These results demonstrate that statins, a class of drugs already approved by the US Food and Drug Administration, might be repurposed for the management of FLT3 mutant acute myeloid leukemia cases either alone or in conjunction with FLT3 TKI.

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    • "Inhibition of STAT5 and STAT3 was also reported [73]. Fluvastatin was able to impair glycosylation of FLT3, one of the most frequently mutated genes in acute myeloid leukemia (AML), treated with tyrosine kinase inhibitors, thus leading to the loss of its surface expression and induction of cell death in vitro and in vivo [74]. Also a combination of statins and ionizing radiations has been reported successful in the suppression of lung tumors [75]. "
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    • "In addition, mevalonate, and isoprenoid intermediates such as geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate (FPP) in the cholesterol synthesis pathway are also depleted after statin treatment [44]. Another intermediate, dolichol, an essential substrate for protein N-glycosylation, is also blocked by statins [45,46]. Considering that GBMs are highly proliferative taking up large quantities of cholesterol, potentially they may be vulnerable to statin treatment [47,48]. "
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