Gene expression profiling of homologous recombination repair pathway indicates susceptibility for olaparib treatment in malignant pleural mesothelioma in vitro
Sabrina Borchert,
Michael Wessolly,
Jan Schmeller,
Elena Mairinger,
Jens Kollmeier,
Thomas Hager,
Thomas Mairinger,
Thomas Herold,
Daniel C. Christoph,
Robert F. H. Walter,
Wilfried E. E. Eberhardt,
Till Plönes,
Jeremias Wohlschlaeger,
Clemens Aigner,
Kurt Werner Schmid,
Fabian D. Mairinger
Affiliations
Sabrina Borchert
Institute of Pathology, University Hospital Essen, University of Duisburg-Essen
Michael Wessolly
Institute of Pathology, University Hospital Essen, University of Duisburg-Essen
Jan Schmeller
Institute of Pathology, University Hospital Essen, University of Duisburg-Essen
Elena Mairinger
Institute of Pathology, University Hospital Essen, University of Duisburg-Essen
Jens Kollmeier
Department of Pneumology, Helios Klinikum Emil von Behring
Thomas Hager
Institute of Pathology, University Hospital Essen, University of Duisburg-Essen
Thomas Mairinger
Department of Pathology, Helios Klinikum Emil von Behring
Thomas Herold
Institute of Pathology, University Hospital Essen, University of Duisburg-Essen
Daniel C. Christoph
Department of Medical Oncology, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen
Robert F. H. Walter
Institute of Pathology, University Hospital Essen, University of Duisburg-Essen
Wilfried E. E. Eberhardt
Department of Medical Oncology, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen
Till Plönes
Department of Thoracic Surgery and Thoracic Endoscopy, Ruhrlandklinik, University Hospital Essen, University of Duisburg-Essen
Jeremias Wohlschlaeger
Institute of Pathology, University Hospital Essen, University of Duisburg-Essen
Clemens Aigner
Department of Thoracic Surgery and Thoracic Endoscopy, Ruhrlandklinik, University Hospital Essen, University of Duisburg-Essen
Kurt Werner Schmid
Institute of Pathology, University Hospital Essen, University of Duisburg-Essen
Fabian D. Mairinger
Institute of Pathology, University Hospital Essen, University of Duisburg-Essen
Abstract Background Malignant pleural mesothelioma (MPM) is a tumour arising from pleural cavities with poor prognosis. Multimodality treatment with pemetrexed combined with cisplatin shows unsatisfying response-rates of 40%. The reasons for the rather poor efficacy of chemotherapeutic treatment are largely unknown. However, it is conceivable that DNA repair mechanisms lead to an impaired therapy response. We hypothesize a major role of homologous recombination (HR) for genome stability and survival of this tumour. Therefore, we analysed genes compiled under the term “BRCAness”. An inhibition of this pathway with olaparib might abrogate this effect and induce apoptosis. Methods We investigated the response of three MPM cell lines and lung fibroblasts serving as a control to treatment with pemetrexed, cisplatin and olaparib. Furthermore, we aimed to find possible correlations between response and gene expression patterns associated with BRCAness phenotype. Therefore, 91 clinical MPM samples were digitally screened for gene expression patterns of HR members. Results A BRCAness-dependent increase of apoptosis and senescence during olaparib-based treatment of BRCA-associated-protein 1 (BAP1)-mutated cell lines was observed. The gene expression pattern identified could be found in approx. 10% of patient samples. Against this background, patients could be grouped according to their defects in the HR system. Gene expression levels of Aurora Kinase A (AURKA), RAD50 as well as DNA damage-binding protein 2 (DDB2) could be identified as prognostic markers in MPM. Conclusions Defects in HR compiled under the term BRCAness are a common event in MPM. The present data can lead to a better understanding of the underlaying cellular mechanisms and leave the door wide open for new therapeutic approaches for this severe disease with infaust prognosis. Response to Poly (ADP-ribose)-Polymerase (PARP)-Inhibition could be demonstrated in the BAP1-mutated NCI-H2452 cells, especially when combined with cisplatin. Thus, this combination therapy might be effective for up to 2/3 of patients, promising to enhance patients’ clinical management and outcome.
