Statins Induce Leukemia Cytotoxicity by Preventing FLT3 Glycosylation

Activating mutations in FMS-related tyrosine kinase 3 (FLT3) frequently occur in acute myeloid leukemia (AML) and can be targeted by tyrosine kinase inhibitors (TKI), but resistance mechanisms limit the efficacy of these drugs. FLT3 and other receptors undergo N-linked protein glycosylation that is required for maturation and translocation to the cell surface, suggesting that inhibition of this modification may disrupt receptor kinase activity. Williams and colleagues tested this hypothesis using statins, which target 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) to lower cholesterol production; these drugs also block the generation of dolichol, a mediator of oligosaccharide transfer during glycosylation. Treatment of FLT3-dependent leukemia cells with fluvastatin prevented the formation of mature glycosylated FLT3 protein and its subsequent autophosphorylation. This suppression of glycosylation resulted in depletion of cell-surface FLT3 and intracellular accumulation of immature receptors unable to respond to ligand stimulation. Consistent with this, fluvastatin attenuated downstream signaling through the MAPK and AKT pathways, resulting in decreased cell proliferation and induction of apoptosis in leukemia cell lines and primary human AML blast samples. Analogous effects were also observed in cells expressing alternative kinase-activating mutations in FLT3 or other transmembrane receptor kinases known to be glycosylated, such as c-KIT, indicating that statins may broadly affect protein glycosylation. In addition, fluvastatin significantly reduced leukemia cell engraftment and prolonged survival of mice with FLT3-mutant leukemia. Furthermore, fluvastatin-mediated inhibition of glycosylation was sufficient to overcome several mechanisms of FLT3-TKI resistance, including increased TKI IC₅₀ due to elevated FLT3 ligand levels, acquisition of secondary mutations in FLT3, and compensatory stimulation of the interleukin-3 pathway. These findings suggest that statins, which are clinically approved and well tolerated in patients, may synergize with FLT3-TKIs to provide therapeutic benefit to patients with AML.

Williams AB, Li L, Nguyen B, Brown P, Levis M, Small D. Fluvastatin inhibits FLT3 glycosylation in human and murine cells and prolongs survival of mice with FLT3/ITD leukemia. Blood 2012 Aug 27 [Epub ahead of print].