We investigated the activation of
platelet-derived growth factor (
PDGF) receptor A (PDGFRA),
PDGF receptor B (
PDGFRB),
epidermal growth factor receptor (EGFR), and their downstream pathways in
malignant peripheral nerve sheath tumors (MPNSTs). PDGFRA,
PDGFRB, and EGFR were immunohistochemically, biochemically, cytogenetically, and mutationally analyzed along with the detection of their cognate
ligands in 16
neurofibromatosis type 1 (NF1)-related and 11 sporadic MPNSTs. The activation of the downstream receptor pathways was also studied by means of v-akt murine
thymoma viral oncogene homolog (AKT),
extracellular signal-regulated kinase (ERK), and
mammalian target of rapamycin (mTOR) Western blotting experiments, as well as rat
sarcoma viral oncogene homolog (RAS), v-raf murine
sarcoma viral oncogene homolog B1 (BRAF),
phosphoinositide-3-kinase, catalytic, alpha polypeptide (PI3KCA), and
phosphatase and
tensin homolog deleted on chromosome ten (PTEN) mutational analysis and fluorescence in situ hybridization. PDGFRA,
PDGFRB, and EGFR were expressed/activated, with higher levels of EGFR expression/phosphorylation paralleling increasing EGFR gene copy numbers in the NF1-related cases (71%). Autocrine loop activation of these receptors along with their coactivation were suggested by the expression of the cognate
ligands in the absence of mutations and the presence of
receptor tyrosine kinase (RTK) heterodimers, respectively. Both
MPNST groups showed AKT, ERK, and mTOR expression/phosphorylation. No BRAF, PI3KCA, or PTEN mutations were found in either group of MPNSTs, but 18% of the sporadic MPNSTs showed RAS mutations. PTEN
monosomy segregated with the NF1-related cases (50%, p = 0.018), but
PTEN protein was expressed in all but two cases. In conclusion, PDGFRA,
PDGFRB, and EGFR seem to be promising molecular targets for tailored treatments in
MPNST. In particular, the
ligand- and heterodimerization-dependent RTK activation/expression coupled with a downstream signaling phosphorylation, mediated by the upstream receptors or RAS activation, may provide a rationale to apply combined RTK and mTOR inhibitor treatments both to sporadic and NF1-related cases.