前列腺癌
PLK1
癌症研究
有丝分裂
雄激素受体
生物
癌症
癌细胞
细胞周期
细胞生物学
遗传学
作者
Jesse C. Patterson,Andreas Varkaris,Peter J.P. Croucher,Maya Ridinger,Susan L. Dalrymple,Mannan Nouri,Fang Xie,Shohreh Varmeh,Oliver Jonas,Matthew A. Whitman,Sen Chen,Saleh Rashed,Lovemore Makusha,Jun Luo,John T. Isaacs,Mark G. Erlander,David J. Einstein,Steven P. Balk,Michael B. Yaffe
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2022-11-21
卷期号:83 (2): 219-238
被引量:3
标识
DOI:10.1158/0008-5472.can-22-1533
摘要
Abstract Abiraterone is a standard treatment for metastatic castrate-resistant prostate cancer (mCRPC) that slows disease progression by abrogating androgen synthesis and antagonizing the androgen receptor (AR). Here we report that inhibitors of the mitotic regulator polo-like kinase-1 (Plk1), including the clinically active third-generation Plk1 inhibitor onvansertib, synergizes with abiraterone in vitro and in vivo to kill a subset of cancer cells from a wide variety of tumor types in an androgen-independent manner. Gene-expression analysis identified an AR-independent synergy-specific gene set signature upregulated upon abiraterone treatment that is dominated by pathways related to mitosis and the mitotic spindle. Abiraterone treatment alone caused defects in mitotic spindle orientation, failure of complete chromosome condensation, and improper cell division independently of its effects on AR signaling. These effects, although mild following abiraterone monotherapy, resulted in profound sensitization to the antimitotic effects of Plk1 inhibition, leading to spindle assembly checkpoint-dependent mitotic cancer cell death and entosis. In a murine patient-derived xenograft model of abiraterone-resistant metastatic castration-resistant prostate cancer (mCRPC), combined onvansertib and abiraterone resulted in enhanced mitotic arrest and dramatic inhibition of tumor cell growth compared with either agent alone. Overall, this work establishes a mechanistic basis for the phase II clinical trial (NCT03414034) testing combined onvansertib and abiraterone in mCRPC patients and indicates this combination may have broad utility for cancer treatment. Significance: Abiraterone treatment induces mitotic defects that sensitize cancer cells to Plk1 inhibition, revealing an AR-independent mechanism for this synergistic combination that is applicable to a variety of cancer types.
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