Malignant peripheral nerve sheath tumors (MPNSTs) are
soft tissue sarcomas that occur spontaneously, or from benign
plexiform neurofibromas, in the context of the
genetic disorder Neurofibromatosis Type 1 (NF1). The current standard treatment includes surgical resection, high-dose
chemotherapy, and/or radiation. To date, most targeted
therapies have failed to demonstrate effectiveness against
plexiform neurofibromas and MPNSTs. Recently, several studies suggested that the mTOR and MAPK pathways are involved in the formation and progression of MPNSTs.
Everolimus (
RAD001) inhibits the mTOR and is currently FDA approved for several types of solid
tumors.
PD-0325901 (PD-901) inhibits
MEK, a component of the MAPK pathway, and is currently in clinical trials. Here, we show in vitro than
MPNST cell lines are more sensitive to inhibition of cellular growth by
Everolimus and PD-901 than immortalized human Schwann cells. In combination, these drugs synergistically inhibit cell growth and induce apoptosis. In two genetically engineered mouse models of
MPNST formation, modeling both sporadic and NF1-associated MPNSTs,
Everolimus, or PD-901 treatment alone each transiently reduced
tumor burden and size, and extended lifespan. However, prolonged treatment of each single agent resulted in the development of resistance and reactivation of target pathways. Combination
therapy using
Everolimus and PD-901 had synergistic effects on reducing
tumor burden and size, and increased lifespan. Combination
therapy allowed persistent and prolonged reduction in signaling through both pathways. These data suggest that co-targeting mTOR and
MEK may be effective in patients with sporadic or NF1-associated MPNSTs.