Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer

被引：219

作者：

Quereda, Victor ^{[1
]}

Bayle, Simon ^{[1
]}

Vena, Francesca ^{[1
]}

Frydman, Sylvia M. ^{[1
]}

Monastyrskyi, Andrii ^{[1
]}

Roush, William R. ^{[2
]}

Duckett, Derek R. ^{[1
]}

机构：

[1] H Lee Moffitt Canc Ctr & Res Inst, Dept Drug Discovery, Tampa, FL 33612 USA

[2] Scripps Res Inst, Dept Chem, Jupiter, FL 33458 USA

来源：

CANCER CELL | 2019年 / 36卷 / 05期

关键词：

DNA-DAMAGE; POLY(ADP-RIBOSE) POLYMERASE; TRANSCRIPTION REGULATION; CDK12; KINASE; PHOSPHORYLATION; EXPRESSION; DISEASE; TRANSFORMATION; MAINTENANCE;

D O I：

10.1016/j.ccell.2019.09.004

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Epigenetic regulation enables tumors to respond to changing environments during tumor progression and metastases and facilitates treatment resistance. Targeting chromatin modifiers or catalytic effectors of transcription is an emerging anti-cancer strategy. The cyclin-dependent kinases (CDKs) 12 and 13 phosphorylate the C-terminal domain of RNA polymerase II, regulating transcription and co-transcriptional processes. Here we report the development of SR-4835, a highly selective dual inhibitor of CDK12 and CDK13, which disables triple-negative breast cancer (TNBC) cells. Mechanistically, inhibition or loss of CDK12/CDK13 triggers in-tronic polyadenylation site cleavage that suppresses the expression of core DNA damage response proteins. This provokes a "BRCAness'' phenotype that results in deficiencies in DNA damage repair, promoting synergy with DNA-damaging chemotherapy and PARP inhibitors.

引用

页码：545 / +

页数：21

共 51 条

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Zhang, Xiaomei ;

Claerhout, Sofie ;

Prat, Aleix ;

Dobrolecki, Lacey E. ;

Petrovic, Ivana ;

Lai, Qing ;

Landis, Melissa D. ;

Wiechmann, Lisa ;

Schiff, Rachel ;

Giuliano, Mario ;

Wong, Helen ;

Fuqua, Suzanne W. ;

Contreras, Alejandro ;

Gutierrez, Carolina ;

Huang, Jian ;

Mao, Sufeng ;

Pavlick, Anne C. ;

Froehlich, Amber M. ;

Wu, Meng-Fen ;

Tsimelzon, Anna ;

Hilsenbeck, Susan G. ;

Chen, Edward S. ;

Zuloaga, Pavel ;

Shaw, Chad A. ;

Rimawi, Mothaffar F. ;

Perou, Charles M. ;

Mills, Gordon B. ;

Chang, Jenny C. ;

Lewis, Michael T. .

CANCER RESEARCH, 2013, 73 (15) :4885-4897

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