Molecular Signatures for Combined Targeted Treatments in Diffuse Malignant Peritoneal Mesothelioma.

Belfiore Belfiore,Kusamura Kusamura,Conca Conca,Deraco Deraco,Perrone Perrone,Guaglio Guaglio,Volpi Volpi,Dallera Dallera,Baratti Baratti,Gloghini Gloghini,Bozzi Bozzi,Busico Busico,Pilotti Pilotti,D.cabras D.Cabras,Brich Brich,Capone Capone

doi:10.3390/ijms20225817

Abstract

Background—There are currently no effective therapies for diffuse malignant peritoneal mesothelioma (DMPM) patients with disease recurrence. In this study, we investigated the biology of DMPM by analyzing the EGFR family, Axl, and MET, in order to assess the presence of cross-talk between these receptors, suggesting the effectiveness of combined targeted treatments in DMPM. Method—We analyzed a series of 22 naïve epithelioid DMPM samples from a single institute, two of which showed higher-grade malignancy (“progressed”). EGFR, HER2, HER3, Axl, and MET activation and expression were investigated by biochemical analysis, real-time PCR immunofluorescence, immunohistochemistry, next-generation sequencing, miRNA, and mRNA in situ hybridization. Results—In most DMPMs, a strong EGFR activation was associated with HER2, HER3, Axl, and MET co-activation, mediated mainly by receptor heterodimerization and autocrine-paracrine loops induced by the expression of their cognate ligands. Axl expression was downregulated by miRNA34a. Mutations in MET Sema domain were exclusively found in two “progressed” DMPMs, and the combined Axl and MET inhibition reduced cellular motility in a DMPM cell line obtained from a “progressed” DMPM. Conclusion—The results indicate that the coordinated activity of multiple cross-talks between RTKs is directly involved in the biology of DMPM, suggesting the combined inhibition of PIK3 and mTOR as an effective strategy that may be easily implemented in clinical practice, and indicating that the combined inhibition of EGFR/HER2 and HER3 and of Axl and MET deserves further investigation.

Highlights

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and locally aggressive neoplasm that is traditionally considered to be a rapidly lethal disease
We investigated the biology of diffuse malignant peritoneal mesothelioma (DMPM) by analyzing the epidermal growth factor receptor (EGFR) family, Axl, and Met/hepatocyte growth factor receptor (MET), in order to assess the presence of cross-talk between these receptors, suggesting the effectiveness of combined targeted treatments in DMPM
In most DMPMs, a strong EGFR activation was associated with HER2, HER3, Axl, and MET co-activation, mediated mainly by receptor heterodimerization and autocrine-paracrine loops induced by the expression of their cognate ligands

Summary

Introduction

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and locally aggressive neoplasm that is traditionally considered to be a rapidly lethal disease. Studies on DMPM genomic profiling have improved our understanding of the molecular biology of this rare tumor and have identified potential therapeutic targets These studies have shown that DMPM is characterized by mutations in BRCA1 associated protein 1 (BAP 1), Neurofibromin 2 (NF2), DEAD-Box Helicase 3 X-Linked (DDX3X), SET Domain Containing 2, Histone Lysine Methyltransferase (SETD2) genes, as well as by the loss of 3p21 locus, which includes chromatin modifiers and epigenetic regulatory genes such as BAP1, SETD2, SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily C member (SMARCC1), and Polybromo 1 (PBRM1) [6,7]. Conclusion—The results indicate that the coordinated activity of multiple cross-talks between RTKs is directly involved in the biology of DMPM, suggesting the combined inhibition of PIK3 and mTOR as an effective strategy that may be implemented in clinical practice, and indicating that the combined inhibition of EGFR/HER2 and HER3 and of Axl and MET deserves further investigation

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