Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer
Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer
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DOI：
10.1016/j.ccell.2019.09.004
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发表时间：
2019-11-11
期刊：
影响因子：
50.3
通讯作者：
Duckett, Derek R.
中科院分区：
文献类型：
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作者：
Quereda, Victor;Bayle, Simon;Duckett, Derek R.
表观遗传调控使肿瘤在肿瘤进展和转移过程中对变化的环境作出反应，并促进治疗耐药性。靶向染色质修饰物或转录催化效应物是一种新兴的抗癌策略。细胞周期蛋白依赖性激酶（CDKs） 12和13磷酸化RNA聚合酶II的c端结构域，调节转录和共转录过程。在这里，我们报道了SR-4835的发展，这是一种CDK12和CDK13的高选择性双重抑制剂，可使三阴性乳腺癌（TNBC）细胞失活。从机制上讲，CDK12/CDK13的抑制或缺失会触发电子内聚腺苷化位点的切割，从而抑制核心DNA损伤反应蛋白的表达。这引发了一种“BRCAness”表型，导致DNA损伤修复缺陷，促进与DNA损伤化疗和PARP抑制剂的协同作用。
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.