Gene expression profiling of homologous recombination repair pathway indicates susceptibility for olaparib treatment in malignant pleural mesothelioma in vitro

Abstract

BackgroundMalignant 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.MethodsWe 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.ResultsA 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.ConclusionsDefects 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.Electronic supplementary materialThe online version of this article (10.1186/s12885-019-5314-0) contains supplementary material, which is available to authorized users.

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

“…For example, we have reported that PARP inhibition (by olaparib and niraparib) sensitized tumor cells that have been exposed to ionizing radiation by producing a more robust senescent response associated with increased DNA double-stranded damage [130]. These results were recently confirmed by showing that olaparib, the first FDA-approved PARP inhibitor, results in a robust senescent response (rather than apoptosis) when preceded by genotoxic stress induced by cisplatin or pemetrexed [146].…”

Systemic therapies for intrahepatic cholangiocarcinoma

“…87 Likewise, BAP1 mutations have also been linked to cellular sensitivity to apoptosis following treatment with the PARP inhibitor olaparib. 88 Trials examining PARP inhibitors in patients with these cellular defects are currently ongoing and eagerly awaited.…”

Panorama epigenético del mesotelioma pleural maligno

“…BAP1 funciona para estabilizar el BRCA-1 y promover el reclutamiento dependiente de poli (ADP-Ribosa) del complejo de poliquial deubiquitinasa PR-DUB a los sitios de daño del ADN. [104][105][106] Esta actividad depende de la actividad de la deubiquitinasa y de la fosforilación de BAP1. 107 Las mutaciones BAP1, que siempre parecen manifestarse como pérdida de función, disminuyen los niveles de BRCA-1 e inhiben la reparación del ADN de doble cadena.…”

“…Estas estrategias podrían mejorar las respuestas a cisplatino/pemetrexed en pacientes con MPM. 106 Estos hallazgos, junto con las observaciones recientes del microambiente, tienen un impacto en el resultado de los pacientes con MPM para una combinación convincente de inmunoterapias epigenéticas para estas neoplasias. [106][107] conclusIones El MPM es una enfermedad con incidencia baja, pero con un comportamiento agresivo, cuya supervivencia no va más allá de 12 meses una vez hecho el diagnóstico.…”

“…106 Estos hallazgos, junto con las observaciones recientes del microambiente, tienen un impacto en el resultado de los pacientes con MPM para una combinación convincente de inmunoterapias epigenéticas para estas neoplasias. [106][107] conclusIones El MPM es una enfermedad con incidencia baja, pero con un comportamiento agresivo, cuya supervivencia no va más allá de 12 meses una vez hecho el diagnóstico. Su origen se ha relacionado a la exposición crónica del asbesto como factor principal, siendo este componente esencial en los cambios estructurales a nivel molecular; y de cuyos estudios hay mucha evidencia acerca de su comportamiento genético y en menor medida epigenético, lo que le confiere un comportamiento bastante heterogéneo.…”