Targeting DNA damage deficient mesotheliomas via synthetic lethal disruption of DNA double-strand repair

Given that there is still lack of effective targeted therapy against relapsed malignant pleural mesothelioma (MPM), long latency of this disease and asbestos being used in several non-European countries, the MPM will remain heath issue for decades to come. Therefore, it is a pressing need establish strategies that can avail underlying vulnerabilities to optimise treatments against relapsed MPM and improve patient outcomes. Due to the loss of DNA repair components of Homologous recombination repair (HRR) mesotheliomas rely on Poly (ADP-ribose) polymerase (PARP)-related single-strand break repair pathway. Mesotheliomas tend to harbour HRR deficiency, and thus provide a therapeutic avenue to eliminate malignant cells selectively. Consequently, to test the hypothesis that disruption of homologous recombination DNA repair pathway in malignant pleural mesotheliomas can be therapeutically explored via PARP inhibition (rucaparib) to induce synthetic lethality, we used in vitro, ex vivo and in vivo models. BAP1 is an HRR-associated protein. Approximately 60% of MPMs harbour BAP1 alteration, therefore in the view of the prominence of this tumour suppressor gene, BAP1 could be a potential predictive therapeutic biomarker. Indeed, BAP1 loss of function has been found to be common in the current study. However, it did not render sensitivity to rucaparib in MPM cell lines, explants, nor patients. Nevertheless, FAAP20 loss consistently appeared to correlate with sensitivity to rucaparib in our MPMs models. Moreover, our findings also suggest that platinumbased therapy could be potentially used as a predictor for rucaparib response in MPM patients.</p

BAP1 loss induces mitotic defects in mesothelioma cells through BRCA1-dependent and independent mechanisms

This dataset includes the text, figures and supplementary material associated with the Oncogene submission MS#ONC-2022-0172