Co-targeting the MAPK and PI3K/AKT/mTOR pathways in two genetically engineered mouse models of schwann cell tumors reduces tumor grade and multiplicity

Abstract

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.

STAT3 and HIF1α Signaling Drives Oncogenic Cellular Phenotypes in Malignant Peripheral Nerve Sheath Tumors

“…mTORC1 activation has also been implicated in MPNST tumorigenesis (33). Although mTORC1 inhibitors have shown some success in NF1 patients (40,41), tumor regression did not occur via the usual mechanisms, with the proangiogenic factor HIF1a remaining elevated under rapamycin treatment (33). Of interest, we also observed that HIF1a protein levels were not completely ablated with rapamycin treatment in all four MPNST cell lines tested.…”

The Challenge of Cancer Genomics in Rare Nervous System Neoplasms

“…Indeed, the simultaneous activation and intrafamily functional redundancy of Ras proteins in NF1-null MPNST cells suggests that it will be difficult to target these proteins therapeutically. Consequently, some laboratories have asked whether targeting signaling pathways downstream of Ras such as mitogen-activated protein extracellular signal-related kinase (ERK) kinase (MEK) 31,32 and the phosphatidylinositol 3-kinase (PI3K)-Akt-TSC2-mammalian target of rapamycin (mTOR)-S6 kinase 33,34 would be more effective therapeutically. Although initial results indicate that this is the case, note that the full repertoire of Ras-dependent signaling pathways activated in NF1-null peripheral nerve sheath tumors has not yet been defined.…”

Rapamycin Prolongs Cardiac Allograft Survival in a Mouse Model by Inducing Myeloid-Derived Suppressor Cells

“…Interestingly, studies show that inhibiting mTOR activates the Raf/mitogen-activated protein kinase kinase (MEK)/ extracellular signal regulated kinase (ERK) pathway (17)(18)(19). Indeed, dual inhibition of the mTOR and Raf/MEK/ERK signaling pathways is an attractive therapy for malignant tumors (20,21).…”