Frequent EGFR Positivity and Overexpression in High-Grade Areas of Human MPNSTs

Abstract

Malignant peripheral nerve sheath tumours (MPNSTs) are highly malignant and resistant. Transformation might implicate up regulation of epidermal growth factor receptor (EGFR). Fifty-two MPNST samples were studied for EGFR, Ki-67, p53, and survivin expression by immunohistochemistry and for EGFR amplification by in situ hybridization. Results were correlated with clinical data. EGFR RNA was also quantified by RT-PCR in 20 other MPNSTs and 14 dermal neurofibromas. Half of the patients had a neurofibromatosis type 1 (NF1). EGFR expression, detected in 86% of MPNSTs, was more frequent in NF1 specimens and closely associated with high-grade and p53-positive areas. MPNSTs expressed more EGFR transcripts than neurofibromas. No amplification of EGFR locus was observed. NF1 status was the only prognostic factor in multivariate analysis, with median survivals of 18 and 43 months for patients with or without NF1. Finally, EGFR might become a new target for MPNSTs treatment, especially in NF1-associated MPNSTs.

Dual targeting of AKT and mammalian target of rapamycin: A potential therapeutic approach for malignant peripheral nerve sheath tumor

“…These findings suggest that, whereas neurofibromin loss might contribute to AKT/mTOR deregulation, other molecular derangements acquired throughout the tumorigenic process may also be relevant. For example, among other potential mechanisms, overexpression and activation of the EGFR and c-Met tyrosine kinase receptors as well as loss of PTEN expression have been identified in MPNST (25)(26)(27)(28)(33)(34)(35)(36). No difference in AKT/mTOR activation could be identified when we compared NF1-associated and sporadic MPNST samples.…”

Survivin Is a Viable Target for the Treatment of Malignant Peripheral Nerve Sheath Tumors

“…Overexpression of survivin mRNA in MPNST compared to neurofibroma has been observed by three independent groups (16, 18, 19). Finally, a recent immunohistochemistry-based study demonstrated survivin protein expression in 52 human MPNST samples (20). Building on these initial observations, the current study sought to further determine the potential role of survivin as a MPNST biomarker, to elucidate the functional consequences of survivin over-expression in these tumors, and, most importantly, to assess the efficacy of survivin blockade as an anti-MPNST therapeutic strategy.…”

Cancer of the Peripheral Nerve in Neurofibromatosis Type 1

“…Multiple studies have implicated EGFR as a key oncogenic target in MPNST that is overexpressed in more than two-thirds of patients and associated with high-grade, p53 positivity and invasiveness [21,29,[34][35][36][37][38]. Despite a sound rationale and the fact that MPNST derived from patients and NF1 +/-…”

“…+/-mice can be stimulated by epidermal growth factor and inhibited by EGFR inhibitors [36][37][38], a phase II trial with EGFR inhibitor erlotinib, the first targeted agent used in a NF1-associated MPNST, largely failed [39]. Other inhibitors have targeted PDGFR, which also shows an increased expression of both proteins in MPNSTs and carries prognostic relevance [29,40,41].…”