Molecular Signatures for Combined Targeted Treatments in Diffuse Malignant Peritoneal Mesothelioma

Our plain-English summary of Molecular Signatures for Combined Targeted Treatments in Diffuse Malignant Peritoneal Mesothelioma, by A. Belfiore, A. Busico, F. Bozzi, et al (International Journal of Molecular Sciences, 2019).

The study

• Authors: A. Belfiore, A. Busico, F. Bozzi, S. Brich, E. Dallera, E. Conca, I. Capone, A. Gloghini, C.C. Volpi, A.D. Cabras, S. Pilotti, D. Baratti, M. Guaglio, M. Deraco, S. Kusamura, F. Perrone
• Journal: International Journal of Molecular Sciences
• Published: 2019;20(22)
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study examined tumor samples of diffuse malignant peritoneal mesothelioma (DMPM), a cancer of the lining of the abdomen. The samples came from 22 patients (5 women and 17 men, aged 47 to 77) treated with surgery and heated chemotherapy inside the abdomen between 2011 and 2014 at a cancer institute in Milan, Italy. All tumors were epithelioid. Two were classed as "progressed" because they looked more malignant. The authors tested the samples for activity of several growth-signal receptors on cells (EGFR, HER2, HER3, Axl and MET). EGFR was active in 16 of 21 samples tested, HER2 in 16 of 22, HER3 in 17 of 22, Axl in 18 of 21 and MET in 11 of 21. MET mutations were found only in the two "progressed" tumors. The authors also used a cell line that had been grown earlier from one progressed tumor. In those cells, a drug blocking both Axl and MET reduced cell movement in a scratch test, but it slowed cell growth only at higher doses. The authors concluded that several interacting receptors are involved in DMPM biology and that combined drug treatments might be effective and are worth further clinical study. The article does not discuss asbestos.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (molecular pathology) study of surgical tumor specimens, plus experiments on a previously established tumor-derived cell line
• Who was studied: Epithelioid diffuse malignant peritoneal mesothelioma specimens from 22 patients (5 female, 17 male; ages 47 to 77, median 64) treated with cytoreductive surgery and HIPEC between 2011 and 2014 at the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Two cases were classified as "progressed". Not every test was run on all 22 samples.
• Main results:
  • EGFR phosphorylation (activation) was found in 16 of 21 (76%) frozen tumor samples, and EGFR expression in 20 of 21 (95%).
  • HER2 phosphorylation was found in 16 of 22 (73%) cases.
  • HER3 phosphorylation was found in 17 of 22 (77%) cases, and HER3 expression in 21 (95%).
  • Axl phosphorylation was found in 18 of 21 cases (86%).
  • MET activation was found in 11 of 21 (52%) cases and MET expression in 15 of 21 (71%).
  • MET mutations were found only in the two "progressed" DMPM cases.
  • The SSL1 cell line used in the experiments had been obtained previously from progressed case #16.
  • In the SSL1 cell line from progressed case #16, the Axl/MET inhibitor BMS-777607 at 2 µM and 5 µM reduced repopulation of the scratch area after 24 hours compared with untreated and DMSO controls.
  • In the same cell line, BMS-777607 lowered proliferation compared with untreated cells only at the higher doses (5 and 10 µM).
  • In the few cases examined by in situ hybridization, miRNA 34a levels ran opposite to Axl expression.
• The authors' conclusion: The authors concluded that the coordinated activity of multiple interacting receptor tyrosine kinases is involved in DMPM biology. They suggested that combined inhibition of EGFR/HER2 and HER3, or of Axl and MET, or of PIK3 and mTOR might be an effective treatment strategy worth further clinical investigation.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, EGFR, Epithelioid, HER2, Immunohistochemistry, Next-Generation Sequencing (NGS).

Related studies

• miR-550a-3p is a prognostic biomarker and exerts tumor-suppressive functions by targeting HSP90AA1 in diffuse malignant peritoneal mesothelioma — R. El Bezawy, S. Percio, et al. (2022)
• Cytoreductive surgery with selective versus complete parietal peritonectomy followed by hyperthermic intraperitoneal chemotherapy in patients with diffuse malignant peritoneal mesothelioma: a controlled study — D. Baratti, S. Kusamura, et al. (2012)
• Complex Immune Contextures Characterise Malignant Peritoneal Mesothelioma: Loss of Adaptive Immunological Signature in the More Aggressive Histological Types — M. Tazzari, S. Brich, et al. (2018)
• Lymph node metastases in diffuse malignant peritoneal mesothelioma — D. Baratti, S. Kusamura, et al. (2010)
• FASN for diffuse malignant peritoneal mesothelioma: a prognostic biomarker after CRS+HIPEC and a therapeutic target — V. Doldi, C.M. Ciniselli, et al. (2026)
• Molecular characterization of diffuse malignant peritoneal mesothelioma — Y.P. Hung, F. Dong, et al. (2020)

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