Inhibition of the serine/threonine kinase BUB1 reverses taxane resistance in prostate cancer

Abstract

Men with incurable castration resistant prostate cancer (CRPC) are typically treated with taxanes; however, drug resistance rapidly develops. We previously identified a clinically relevant seven gene network in aggressive CRPC, which includes the spindle assembly checkpoint (SAC) kinase BUB1. Since SAC is deregulated in taxane resistant PC, we evaluated BUB1 and found that it was over-expressed in advanced PC patient datasets and taxane resistant PC cells. Treatment with a specific BUB1 kinase inhibitor re-sensitized resistant CRPC cells, including cells expressing constitutively active androgen receptor (AR) variants, to clinically used taxanes. Consistent with a role of AR variants in taxane resistance, ectopically expressed AR-V7 increased BUB1 levels and reduced sensitivity to taxanes. This work shows that disruption of BUB1 kinase activity reverted resistance to taxanes, which is essential to advancing BUB1 as a potential therapeutic target for intractable chemotherapy resistant CRPC including AR variant driven CRPC, which lacks durable treatment options.