Decreased PP2A expression and activity represent a therapeutic target for plexiform neurofibroma

In neurofibromatosis type 1 (NF1), loss-of-function mutations in the NF1 gene increase activation of the RAS-MEK-ERK signaling cascade, driving tumorigenesis. MEK inhibitors (MEKi) inhibit tumor growth and significantly shrink nerve tumors (neurofibromas). However, MEKi treatment alone fails to eradicate tumor cells, and tumor regrowth occurs after drug withdrawal, highlighting the limitations of targeting the single MEK pathway. An alternative strategy is to promote dephosphorylation of hyperactive kinases that drive tumor growth by enhancing phosphatase activity. We identified deregulated expression of genes encoding subunits of the PP2A phosphatase in neurofibroma and neurofibroma Schwann cells. We confirmed significant reductions in both the expression and enzymatic activity of the PP2A A and C subunits. FTY720, a compound known to restore PP2A phosphatase activity, inhibited tumor sphere formation by mouse and human neurofibroma Schwann cell progenitor cells, suppressed the proliferation of both primary and immortalized neurofibroma-derived Schwann cells, and induced cell apoptosis in vitro. Furthermore, treatment with FTY720-alone or in combination with MEKi-significantly suppressed tumor number and reduced tumor burden in remaining tumors in a murine model of NF1, highlighting the promise of using FTY720 as a novel therapeutic strategy in NF1.