P1.06-12 Defects in Homologous Recombination Repair Indicates Susceptibility for Olaparib Treatment in Malignant Pleural Mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is a tumour with dismal prognosis. Chemotherapeutic treatment with pemetrexed combined with cisplatin shows unsatisfying response-rates of 40%. The reasons for the rather poor efficacy remain 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 expression levels of genes compiled under the term “BRCAness”. An inhibition of this pathway with olaparib might abrogate this effect and induce apoptosis. We evaluated 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 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. We observed a BRCAness-dependent increase of apoptosis and senescence during olaparib-based treatment of BRCA-associated-protein 1 (BAP1)-mutated cell lines. 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. Defects in HR compiled under the term BRCAness are a common event in MPM. The present data may improve the understanding of underlaying cellular mechanisms and open new possibilities for modern therapeutic approaches for this severe disease. Response to Poly (ADP-ribose)-Polymerase (PARP)-Inhibition could be demonstrated in the BAP1-mutated NCI-H2452 cells, especially when combined with cisplatin. This combination therapy might be effective for up to 2/3 of patients, promising to enhance patients’ clinical management and outcome.