Plk1 Inhibitors and Abiraterone Synergistically Disrupt Mitosis and Kill Cancer Cells of Disparate Origin Independently of Androgen Receptor Signaling

被引：14

作者：

Patterson, Jesse C. ^{[1
]}

Varkaris, Andreas ^{[2
,3
]}

Croucher, Peter J. P. ^{[4
]}

Ridinger, Maya ^{[4
]}

Dalrymple, Susan ^{[5
,6
]}

Nouri, Mannan ^{[3
]}

Xie, Fang ^{[3
]}

Varmeh, Shohreh ^{[1
]}

Jonas, Oliver ^{[7
]}

Whitman, Matthew A. ^{[1
]}

Chen, Sen ^{[3
]}

Rashed, Saleh ^{[1
]}

Makusha, Lovemore ^{[1
]}

Luo, Jun ^{[5
,6
]}

Isaacs, John T. ^{[5
,6
]}

Erlander, Mark G. ^{[4
]}

Einstein, David J. ^{[3
]}

Balk, Steven P. ^{[3
]}

Yaffe, Michael B. ^{[1
,8
,9
]}

机构：

[1] David H Koch Inst Integrat Canc Res, MIT, Ctr Precis Canc Med, Dept Biol & Biol Engn, Cambridge, MA USA

[2] Harvard Med Sch, Massachusetts Gen Hosp Canc Ctr, Boston, MA USA

[3] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Med Oncol, Boston, MA USA

[4] Cardiff Oncol Inc, San Diego, CA USA

[5] Johns Hopkins Univ, James Buchanan Brady Urol Inst, Dept Urol, Sch Med, Baltimore, MD USA

[6] Johns Hopkins Univ, Sidney Kimmel Compre hens Canc Ctr, Dept Oncol, Sch Med, Baltimore, MD USA

[7] Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, Boston, MA USA

[8] NCI, NIH, Surg Oncol Program, Bethesda, MD USA

[9] Koch Inst Integrat Canc Biol, MIT, Dept Biol & Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA

来源：

CANCER RESEARCH | 2023年 / 83卷 / 02期

基金：

美国国家卫生研究院;

关键词：

RESISTANT PROSTATE-CANCER; POLO-LIKE KINASE-1; DRUG-COMBINATIONS; STEROID-SYNTHESIS; PHOSPHORYLATION; ENZALUTAMIDE; MECHANISMS; BLOCKADE; DYNAMICS; AGENTS;

D O I：

10.1158/0008-5472.CAN-22-1533

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 sen-sitization 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 abir-aterone 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.

引用

页码：219 / 238

页数：20

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