Related Experiment Video
Updated: Jan 3, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Molecular Signatures for Combined Targeted Treatments in Diffuse Malignant Peritoneal Mesothelioma
Antonino Belfiore1, Adele Busico1, Fabio Bozzi1
1Laboratory of Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy.
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.
Insights
Effective therapies are lacking for recurrent diffuse malignant peritoneal mesothelioma (DMPM). This study reveals receptor tyrosine kinase (RTK) cross-talk in DMPM, suggesting combined targeted treatments like Axl and MET inhibition show promise for this rare cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Diffuse malignant peritoneal mesothelioma (DMPM) lacks effective treatments for recurrent disease.
- Understanding DMPM biology is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To investigate the biological mechanisms of DMPM by analyzing EGFR family, Axl, and MET signaling pathways.
- To assess cross-talk between these receptors and evaluate potential combined targeted treatments.
Main Methods:
- Analysis of 22 epithelioid DMPM samples.
- Investigation of EGFR, HER2, HER3, Axl, and MET using biochemical assays, PCR, immunofluorescence, immunohistochemistry, NGS, and in situ hybridization.
- Evaluation of miRNA and mRNA expression, including miRNA34a's role in Axl regulation.
Main Results:
- Strong EGFR activation correlated with HER2, HER3, Axl, and MET co-activation in most DMPMs, mediated by receptor heterodimerization and ligand-induced loops.
- Axl expression was downregulated by miRNA34a.
- MET Sema domain mutations were found in progressed DMPMs; combined Axl and MET inhibition reduced DMPM cell motility.
Conclusions:
- Coordinated cross-talk between multiple receptor tyrosine kinases (RTKs) drives DMPM biology.
- Combined inhibition of PIK3 and mTOR is a potential clinical strategy.
- Combined inhibition of EGFR/HER2, HER3, Axl, and MET warrants further investigation for DMPM treatment.
