Martinez Maria J, Lyles Rolando D Z, Peinetti Nahuel, Grunfeld Alex M, Burnstein Kerry L
Department of Molecular & Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.
iScience. 2023 Aug 18;26(9):107681. doi: 10.1016/j.isci.2023.107681. eCollection 2023 Sep 15.
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.
患有无法治愈的去势抵抗性前列腺癌（CRPC）的男性通常接受紫杉烷类药物治疗；然而，耐药性会迅速产生。我们之前在侵袭性CRPC中鉴定出一个具有临床相关性的七基因网络，其中包括纺锤体组装检查点（SAC）激酶BUB1。由于SAC在紫杉烷耐药的前列腺癌中失调，我们对BUB1进行了评估，发现它在晚期前列腺癌患者数据集和紫杉烷耐药的前列腺癌细胞中过度表达。用一种特异性BUB1激酶抑制剂进行治疗可使耐药的CRPC细胞，包括表达组成型活性雄激素受体（AR）变体的细胞，对临床使用的紫杉烷类药物重新敏感。与AR变体在紫杉烷耐药中的作用一致，异位表达的AR-V7增加了BUB1水平并降低了对紫杉烷类药物的敏感性。这项研究表明，破坏BUB1激酶活性可逆转对紫杉烷类药物的耐药性，这对于将BUB1推进为治疗难治性化疗耐药CRPC（包括AR变体驱动的CRPC，目前缺乏持久的治疗选择）的潜在治疗靶点至关重要。
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