Sara Busacca, Laura O'Regan, Anita Singh, Annabel J Sharkey, Alan G Dawson, Joanna Dzialo, Aimee Parsons, Neelam Kumar, Laurel M Schunselaar, Naomi Guppy, Apostolos Nakas, Michael Sheaff, Aaron S Mansfield, Sam M Janes, Paul Baas, Andrew M Fry, Dean A Fennell
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 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 codepletion 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...
February 2021: Molecular Cancer Therapeutics