Mitogen signal-associated pathways, energy metabolism regulation, and mediation of tumor immunogenicity play essential roles in the cellular response of malignant pleural mesotheliomas to platinum-based treatment: a retrospective study

Alexander Mathilakathu; Sabrina Borchert; Michael Wessolly; Elena Mairinger; Hendrik Beckert; Julia Steinborn; Thomas Hager; Daniel C Christoph; Jens Kollmeier; Jeremias Wohlschlaeger; Thomas Mairinger; Kurt Werner Schmid; Robert F H Walter; Luka Brcic; Fabian D Mairinger

doi:10.21037/tlcr-21-201

Mitogen signal-associated pathways, energy metabolism regulation, and mediation of tumor immunogenicity play essential roles in the cellular response of malignant pleural mesotheliomas to platinum-based treatment: a retrospective study

Transl Lung Cancer Res. 2021 Jul;10(7):3030-3042. doi: 10.21037/tlcr-21-201.

Authors

Affiliations

¹ Institute of Pathology, University Hospital Essen, University of Duisburg Essen, Essen, Germany.
² Department of Pulmonary Medicine, University Hospital Essen-Ruhrlandklinik, Essen, Germany.
³ Department of Medical Oncology, Evang. Kliniken Essen-Mitte, Essen, Germany.
⁴ Department of Pneumology, Helios Klinikum Emil von Behring, Berlin, Germany.
⁵ Department of Tissue Diagnostics, Helios Klinikum Emil von Behring, Berlin, Germany.
⁶ Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria.

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare malignant tumor associated with asbestos exposure, with infaust prognosis and overall survival below 20 months in treated patients. Platinum is still the backbone of the chemotherapy protocols, and the reasons for the rather poor efficacy of platinum compounds in MPM remain largely unknown. Therefore, we aimed to analyze differences in key signaling pathways and biological mechanisms in therapy-naïve samples and samples after chemotherapy in order to evaluate the effect of platinum-based chemotherapy.

Methods: The study cohort comprised 24 MPM tumor specimens, 12 from therapy-naïve and 12 from patients after platinum-based therapy. Tumor samples were screened using the NanoString nCounter platform for digital gene expression analysis with an appurtenant custom-designed panel comprising a total of 366 mRNAs covering the most important tumor signaling pathways. Significant pathway associations were identified by gene set enrichment analysis using the WEB-based GEne SeT AnaLysis Toolkit (WebGestalt).

Results: We have found reduced activity of TNF (normalized enrichment score: 2.03), IL-17 (normalized enrichment score: 1.93), MAPK (normalized enrichment score: 1.51), and relaxin signaling pathways (normalized enrichment score: 1.42) in the samples obtained after platinum-based therapy. In contrast, AMPK (normalized enrichment score: -1.58), mTOR (normalized enrichment score: -1.50), Wnt (normalized enrichment score: -1.38), and longevity regulating pathway (normalized enrichment score: -1.31) showed significantly elevated expression in the same samples.

Conclusions: We could identify deregulated signaling pathways due to a directed cellular response to platinum-induced cell stress. Our results are paving the ground for a better understanding of cellular responses and escape mechanisms, carrying a high potential for improved clinical management of patients with MPM.

Keywords: Gene Set Enrichment Analysis; Malignant pleural mesothelioma (MPM); platinum resistance, gene expression.