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- W2570095712 abstract "e13541 Background: Malignant mesothelioma is an aggressive tumor refractory to current therapies and this may be due to intrinsic apoptosis resistance. Vinorelbine has been shown to exhibit useful clinical activity in phase II trials and showed a trend to improved survival as front-line monotherapy in the MS01 phase III study. BRCA1 has been reported to regulate sensitivity to microtubule poisons; however its involvement in regulating apoptosis in Mesothelioma has not been investigated. We have hypothesised that loss of BRCA1 confers resistance to vinorelbine induced apoptosis. Methods: Dose-response curves were generated by vialight assay and caspase-3 activity determined by luminescence assay. Three resistant cell lines were generated by increasing exposure to vinorelbine. Cells were transfected with 10nM non-targeting siRNA or BRCA1/Caspase8 siRNA. The percentage of apoptotic cell population was determined by PI staining and measurement of hypodiploidy. Results: Vinorelbine induced cytotoxicity correlated with BRCA1 expression level in a panel of 6 mesothelioma cell lines. We then investigated the effect BRCA1 silencing on vinorelbine sensitivity. The downregulation blocked caspase-3 activation, PARP cleavage and the percentage of subG1 cell population. Moreover, when cells were selected for resistance to vinorelbine, this was associated with a reduction in BRCA1 expression compared to parental cells. BRCA1 mRNA expression was not altered as shown by gene expression analysis, suggesting a post-transcriptional regulation mechanism. Data obtained in BAX/BAK double negative cells show that vinorelbine mediates toxicity irrespective of a functional mitochondrial apoptosis pathway, however caspase 8 can be activated in these cells; furthermore silencing of Caspase8 induced resistance to apoptosis by vinorelbine. We are addressing the prevalence of BRCA1 negativity in primary mesotheliomas including vinorelbine responders vs non-responders to delineate its potential as a predictive biomarker and will present these results. Conclusions: Our data highlight the BRCA1 as a candidate predictive biomarker for vinorelbine induced apoptosis suggesting a potential utility in personalising therapy with this agent." @default.
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- W2570095712 date "2011-05-20" @default.
- W2570095712 modified "2023-09-27" @default.
- W2570095712 title "BRCA1 expression and efficacy of vinorelbine in malignant mesothelioma." @default.
- W2570095712 doi "https://doi.org/10.1200/jco.2011.29.15_suppl.e13541" @default.
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