Screening of Pleural Mesothelioma Cell Lines for Kinase Activity May Identify New Mechanisms of Therapy Resistance in Patients Receiving Platin-Based Chemotherapy

Sabrina Borchert; Pia-Maria Suckrau; Michael Wessolly; Elena Mairinger; Balazs Hegedus; Thomas Hager; Thomas Herold; Wildfried E E Eberhardt; Jeremias Wohlschlaeger; Clemens Aigner; Agnes Bankfalvi; Kurt Werner Schmid; Robert F H Walter; Fabian D Mairinger

doi:10.1155/2019/2902985

Screening of Pleural Mesothelioma Cell Lines for Kinase Activity May Identify New Mechanisms of Therapy Resistance in Patients Receiving Platin-Based Chemotherapy

J Oncol. 2019 Dec 23:2019:2902985. doi: 10.1155/2019/2902985. eCollection 2019.

Authors

Sabrina Borchert^{1

2}, Pia-Maria Suckrau¹, Michael Wessolly^{1

2}, Elena Mairinger^{1

2}, Balazs Hegedus³, Thomas Hager^{1

2}, Thomas Herold^{1

2}, Wildfried E E Eberhardt^{4

5}, Jeremias Wohlschlaeger^{1

6}, Clemens Aigner³, Agnes Bankfalvi^{1

2}, Kurt Werner Schmid^{1

2}, Robert F H Walter^{1

5}, Fabian D Mairinger^{1

2}

Affiliations

¹ Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
² German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany.
³ Department of Thoracic Surgery and Thoracical Endoscopy, Ruhrlandklinik, West German Lung Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
⁴ Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
⁵ Ruhrlandklinik, West German Lung Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
⁶ Department of Pathology, Diakonissenkrankenhaus Flensburg, Flensburg, Germany.

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare, predominantly asbestos-related and biologically highly aggressive tumor associated with a dismal prognosis. Multimodal therapy consisting of platinum-based chemotherapy is the treatment of choice. The reasons underlying the rather poor efficacy of platinum compounds remain largely unknown. Kinase activity might influence cellular response to these regimens.

Materials and methods: For this exploratory study, we screened MPM cell lines (NCI-H2452, NCI-H2052, and MSTO-211H) differing in response to cisplatin and benign control fibroblasts (MRC-5) for overall phosphorylation patterns as well as kinase activity with respect to cellular response to cisplatin-based therapeutics. We analysed the cell lines for cellular kinases in a high-throughput manner using the highly innovative technique PamGene. Cell state analysis including apoptosis, necrosis, and cell viability was performed by using enzyme activity and fluorescent-based assays.

Results: Cisplatin alters cellular phosphorylation patterns affecting cell cycle, migration, adhesion, signal transduction, immune modulation, and apoptosis. In cisplatin-responsive cell lines, phosphorylation of AKT1 and GSK3B was decreased but could not be influenced in cisplatin-resistant NCI-H2452 cells. Cisplatin-responsive cell lines showed increased phosphorylation levels of JNK1/2/3 but decreased phosphorylation in cisplatin-resistant NCI-H2452 cells.

Conclusion: Kinase phosphorylation and activity might play a crucial role in cellular response to cytostatic agents. Cisplatin influences phosphorylation patterns with distinct features in cisplatin-resistant cells. These alterations exert a significant impact on cell cycle, migration, adhesion, signal transduction, immune modulation, and apoptosis of the respective tumor cells. Based on our results, the induction of p38 or JNK1/3, or inhibition of AKT1 by, for example, BIA-6, might offer a positive synergistic effect by induction of an apoptotic response to cisplatin-based treatment, thus potentially enhancing the clinical outcome of MPM patients.