MEK inhibitors enhance therapeutic response towards ATRA in NF1 associated malignant peripheral nerve sheath tumors (MPNST) <i>in-vitro</i>

<div><p>Objective</p><p>Neurofibromatosis type 1 (NF1) is a hereditary tumor syndrome characterized by an increased risk of malignant peripheral nerve sheath tumors (MPNST). Chemotherapy of MPNST is still insufficient. In this study, we investigated whether human tumor Schwann cells derived from NF1 associated MPNST respond to all-<i>trans</i> retinoic acid (ATRA). We analyzed effects of ATRA and MEK inhibitor (MEKi) combination therapy.</p><p>Methods</p><p>MPNST cell lines S462, T265, NSF1 were treated with ATRA and MEKi U0126 and PD0325901. We assessed cell viability, proliferation, migration, apoptosis and differentiation as well as mRNA expression of <i>RAR</i> and <i>RXR</i> subtypes and ATRA target genes such as <i>CRABP2</i>, <i>CYP26A1</i>, <i>RARB</i> and <i>PDK1</i>. We also analyzed <i>CRABP2</i> methylation in cell lines and performed immunohistochemistry of human MPNST specimens.</p><p>Results</p><p>ATRA therapy reduced viability and proliferation in S462 and T265 cells, accompanied by differentiation, apoptosis and reduced migration. NSF1 cells which lacked <i>RXRG</i> expression did not respond to ATRA. We furthermore demonstrated that ATRA signaling was functional for common targets, and that mRNA expression of <i>CRABP2</i> and its targets was raised by ATRA therapy, whereas alternative pathways via <i>FABP5</i> were not induced. Finally, combination of ATRA and MEKi demonstrated additively reduced viability of T265 and S462 cells.</p><p>Conclusions</p><p>We observed therapeutic effects in two of three MPNST cell lines pronounced by combination therapy. These data point to a potentially successful treatment of MPNST by combined application of ATRA and MEK inhibitors such as U0126 or PD0325901.</p>