BRCA1/MAD2L1 Deficiency Disrupts the Spindle Assembly Checkpoint to Confer Vinorelbine Resistance in Mesothelioma

Abstract

Mesothelioma is a universally lethal cancer lacking effective therapy. The spindle poison vinorelbine exhibits clinical activity in relapsed setting, and in preclinical models requires BRCA1 to initiate apoptosis. However, the mechanisms underlying this regulation and the clinical implications have not been explored. Here we show that BRCA1 silencing abrogated vinorelbine-induced cell cycle arrest, recruitment of BUBR1 to kinetochores, and apoptosis. BRCA1 silencing led to co-depletion of MAD2L1 at the mRNA and protein levels consistent with its status as a transcriptional target of BRCA1. Silencing of MAD2L1 phenocopied BRCA1, and was sufficient to confer resistance to vinorelbine. This was recapitulated in cell lines selected for resistance to vinorelbine, which acquired loss of both BRCA1 and MAD2L1 expression. Following ex-vivo vinorelbine in 20 primary tumour explants, apoptotic response rate was 59% in BRCA1/MAD2L1 positive explants compared with 0% in BRCA1/MAD2L1 negative explants. In 48 patients BRCA1 and/or MAD2L1 loss of expression was not prognostic, however in a subset of patients treated with vinorelbine, survival was shorter for patients lacking BRCA1/MAD2L1 expression compared with double positive patients (5.9 versus 36.7 months, p=0.03). Our data implicates BRCA1/MAD2L1 loss as a putative predictive marker of resistance to vinorelbine in mesothelioma, and warrants prospective clinical evaluation.