Mesothelioma is a universally lethal cancer lacking effective therapy. The spindle poison vinorelbine exhibits clinical activity in the relapsed setting, and in preclinical models requires to initiate apoptosis. However, the mechanisms underlying this regulation and the clinical implications have not been explored. Here, we show that silencing abrogated vinorelbine-induced cell-cycle arrest, recruitment of BUBR1 to kinetochores, and apoptosis. silencing led to codepletion of at the mRNA and protein levels consistent with its status as a transcriptional target of Silencing of phenocopied and was sufficient to confer resistance to vinorelbine. This was recapitulated in cell lines selected for resistance to vinorelbine, which acquired loss of both and expression. Following vinorelbine in 20 primary tumor explants, apoptotic response rate was 59% in -positive explants compared with 0% in -negative explants. In 48 patients, and/or loss of expression was not prognostic; however, in a subset of patients treated with vinorelbine, survival was shorter for patients lacking expression compared with double-positive patients (5.9 vs. 36.7 months, = 0.03). Our data implicate loss as a putative predictive marker of resistance to vinorelbine in mesothelioma and warrant prospective clinical evaluation.