Inhibition of Mps1 kinase enhances taxanes efficacy in castration resistant prostate cancer.
Inhibition of Mps1 kinase enhances taxanes efficacy in castration resistant prostate cancer.
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MPS1激酶的抑制作用增强了抗castratiation抗性前列腺癌中紫杉烷的功效。
DOI：
10.1038/s41419-022-05312-8
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发表时间：
2022-10-13
影响因子：
9
通讯作者：
Ishov, Alexander M.
中科院分区：
文献类型：
--
作者：
Sarwar, Sadia;Morozov, Viacheslav M.;Purayil, Hamsa;Daaka, Yehia;Ishov, Alexander M.
雄激素消融治疗是新诊断的前列腺癌（PC）患者的标准治疗。激素治疗后复发的PC，称为去势抵抗性PC（CRPC），通常表现为转移（mCRPC），是疾病致死的主要原因。mCRPC的少数可用疗法包括紫杉烷类、多西他赛（DTX）和卡巴他赛（CBZ）。可惜，紫杉烷类药物在mCRPC中的临床成功受到高内在和获得性耐药性的限制。因此，开发合理设计的治疗方法来管理耐药性mCRPC疾病仍然至关重要。紫杉烷类对微管超聚合的主要作用是由于纺锤体组装检查点（SAC）的激活而导致的延长的有丝分裂阻滞。紫杉烷敏感细胞最终通过有丝分裂灾难破坏SAC并退出有丝分裂，导致基因组不稳定和增殖受阻。耐药细胞保持有丝分裂阻滞，并且在药物衰变后，恢复有丝分裂和增殖，这是一种耐药机制的基础。在我们的研究中，我们探讨了强制有丝分裂退出以提高紫杉烷疗效的可能性。SAC组分、有丝分裂检查点激酶Mps 1/TTK与小分子抑制剂（Msp 1 i）的失活增强了紫杉烷治疗在2D细胞培养和3D前列腺环境中的功效。从机制上讲，Mps 1抑制迫使细胞有丝分裂灾难在有丝分裂被紫杉烷阻断。雄激素受体（AR）是PC的主要驱动因子，在mCRPC中经常发生突变或截短。值得注意的是，无论AR状态如何，在AR-WT和AR截短的CRPC细胞中，Mps 1 i均显著增强CBZ的细胞毒性。总的来说，我们的数据表明，Mps 1抑制的强制有丝分裂退出增强了紫杉烷的疗效。鉴于几种Mps 1 i目前处于临床试验的不同阶段，我们的结果表明Mps 1是一种新的治疗靶点，可以增强紫杉烷类药物在mCRPC患者中的疗效。
Androgen ablation therapy is the standard of care for newly diagnosed prostate cancer (PC) patients. PC that relapsed after hormonal therapy, referred to as castration-resistant PC (CRPC), often presents with metastasis (mCRPC) and is the major cause of disease lethality. The few available therapies for mCRPC include the Taxanes Docetaxel (DTX) and Cabazitaxel (CBZ). Alas, clinical success of Taxanes in mCRPC is limited by high intrinsic and acquired resistance. Therefore, it remains essential to develop rationally designed treatments for managing therapy-resistant mCRPC disease. The major effect of Taxanes on microtubule hyper-polymerization is a prolonged mitotic block due to activation of the Spindle Assembly Checkpoint (SAC). Taxane-sensitive cells eventually inactivate SAC and exit mitosis by mitotic catastrophe, resulting in genome instability and blockade of proliferation. Resistant cells remain in mitotic block, and, upon drug decay, resume mitosis and proliferation, underlying one resistance mechanism. In our study we explored the possibility of forced mitotic exit to elevate Taxane efficacy. Inactivation of the SAC component, mitotic checkpoint kinase Mps1/TTK with a small molecule inhibitor (Msp1i), potentiated efficacy of Taxanes treatment in both 2D cell culture and 3D prostasphere settings. Mechanistically, Mps1 inhibition forced mitotic catastrophe in cells blocked in mitosis by Taxanes. Androgen receptor (AR), the main driver of PC, is often mutated or truncated in mCRPC. Remarkably, Mps1i significantly potentiated CBZ cytotoxicity regardless of AR status, in both AR-WT and in AR-truncated CRPC cells. Overall, our data demonstrate that forced mitotic exit by Mps1 inhibition potentiates Taxanes efficacy. Given that several Mps1i’s are currently in different stages of clinical trials, our results point to Mps1 as a new therapeutic target to potentiate efficacy of Taxanes in mCRPC patients.
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影响因子：
3.9
作者：
Dehm SM;Tindall DJ
通讯作者：
Tindall DJ
影响因子：
0.2
作者：
Abidi A
通讯作者：
Abidi A
DOI：
10.1083/jcb.200805072
发表时间：
2008-08-25
期刊：
The Journal of cell biology
影响因子：
--
作者：
Brito DA;Yang Z;Rieder CL
通讯作者：
Rieder CL
影响因子：
11.2
作者：
Li, Yingming;Alsagabi, Majid;Dehm, Scott M.
通讯作者：
Dehm, Scott M.
影响因子：
7.7
作者：
Ji, Zhejian;Gao, Haishan;Yu, Hongtao
通讯作者：
Yu, Hongtao