美国莫菲特癌症研究中心Derek R. Duckett小组近日取得一项新成果。他们研制出靶向三阴性乳腺癌中CDK12/CDK13的小分子药物。该研究于10月24日在线发表于《癌细胞》。

研究人员报道了SR-4835分子的研发，这是细胞周期蛋白依赖性激酶（CDK）12和13的高选择性双重抑制剂，可抑制三阴性乳腺癌（TNBC）细胞。从机制上讲，CDK12/CDK13的抑制或丢失会引起内含子多聚腺苷酸化位点断裂，从而抑制关键性DNA损伤反应蛋白的表达。这引起了“ BRCAness”表型，导致DNA损伤修复的缺陷，促进了与破坏DNA的化学疗法和PARP抑制剂的协同作用。

据介绍，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，并增强治疗耐性。靶向转录的染色质修饰剂或催化效应因子是一种新兴的抗癌策略。CDK12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。

附：英文原文

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

Author: Victor Quereda, Simon Bayle, Francesca Vena, Sylvia M. Frydman, Andrii Monastyrskyi, William R. Roush, Derek R. Duckett

Issue&Volume: 2019/10/24

Abstract: 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.

DOI: 10.1016/j.ccell.2019.09.004

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30424-6