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

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Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer.
Cancer Cell ( IF 48.8 ) Pub Date : 2019-10-24 , DOI: 10.1016/j.ccell.2019.09.004
Victor Quereda ₁ , Simon Bayle ₁ , Francesca Vena ₁ , Sylvia M Frydman ₁ , Andrii Monastyrskyi ₁ , William R Roush ₂ , Derek R Duckett ₁

Affiliation

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 intronic 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.

中文翻译：

CDK12 / CDK13在三阴性乳腺癌中的治疗靶向性。

表观遗传调控使肿瘤能够在肿瘤进展和转移过程中对不断变化的环境做出反应，并增强治疗抵抗力。靶向染色质修饰剂或转录的催化效应子是一种新兴的抗癌策略。细胞周期蛋白依赖性激酶（CDK）12和13磷酸化RNA聚合酶II的C末端结构域，调节转录和共转录过程。在这里，我们报告SR-4835的发展，SR-4835是CDK12和CDK13的高度选择性双重抑制剂，可禁用三阴性乳腺癌（TNBC）细胞。从机理上讲，CDK12 / CDK13的抑制或丢失会触发内含子多聚腺苷酸化位点的裂解，从而抑制核心DNA损伤反应蛋白的表达。这会引起“ BRCAness”表型，导致DNA损伤修复的缺陷，

更新日期：2019-11-09

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