PDGFRA, PDGFRB, EGFR, and downstream signalling activation in malignant peripheral nerve sheath tumor

¹ Experimental Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
² Department of Medical and Surgical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
³ Scientific Management, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

^* To whom correspondence should be addressed. E-mail: silvana.pilotti{at}istitutotumori.mi.it.

	Abstract

We investigated the activation of PDGFRA, PDGFRB, EGFR and their downstream pathways in malignant peripheral nerve sheath tumours (MPNSTs). To this, PDGFRA, PDGFRB and EGFR were immunohistochemically, biochemically, cytogenetically and mutationally analysed 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 AKT, ERK and mTOR western blotting experiments, as well as RAS, BRAF, PI3KCA and PTEN mutational analysis and fluorescent in situ hybridisation. PDGFRA, PDGFRB and EGFR were expressed/activated, with higher levels of EGFR expression/phosphorylation parallelling 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 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 heterodimerizationdependent RTK activation/expression coupled with a downstream signalling 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.

Key Words: EGFR, PDGFRA, PDGFRB, mTOR, MPNST

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