CDK12 drives breast tumor initiation and trastuzumab resistance via WNT and IRS1-ErbB-PI3K signaling
CDK12 drives breast tumor initiation and trastuzumab resistance via WNT and IRS1-ErbB-PI3K signaling
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DOI：
10.15252/embr.201948058
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发表时间：
2019-08-30
期刊：
影响因子：
7.7
通讯作者：
Kong, Gu
中科院分区：
文献类型：
--
作者：
Choi, Hee-Joo;Jin, Sora;Kong, Gu
细胞周期蛋白依赖性激酶12（CDK 12）由于其调节人类癌症中DNA损伤修复的能力而成为有效的治疗靶点，但对CDK 12在驱动肿瘤发生中的作用知之甚少。在这里，我们证明了CDK 12作为癌症干细胞（CSC）的新型调节因子促进肿瘤发生，并诱导人类乳腺癌抗HER 2治疗耐药性。乳腺癌患者中由CDK 12和HER 2同时扩增引起的CDK 12高表达与疾病复发和生存率低相关。CDK 12诱导乳腺CSC的自我更新和体内肿瘤起始能力，并且还降低对曲妥珠单抗的易感性。此外，CDK 12激酶活性抑制促进曲妥珠单抗在HER 2（+）肿瘤中的抗癌疗效，并且携带曲妥珠单抗耐药HER 2（+）肿瘤的小鼠显示出对CDK 12抑制剂的敏感性。从机制上讲，CDK 12的催化活性是参与ErbB-PI 3 K-AKT或WNT信号传导级联激活的基因表达所必需的。这些结果表明，CDK 12是HER 2（+）乳腺癌的主要致癌驱动因素和可操作靶点，可替代或增强当前的抗HER 2治疗。
Cyclin-dependent kinase 12 (CDK12) has emerged as an effective therapeutic target due to its ability to regulate DNA damage repair in human cancers, but little is known about the role of CDK12 in driving tumorigenesis. Here, we demonstrate that CDK12 promotes tumor initiation as a novel regulator of cancer stem cells (CSCs) and induces anti-HER2 therapy resistance in human breast cancer. High CDK12 expression caused by concurrent amplification of CDK12 and HER2 in breast cancer patients is associated with disease recurrence and poor survival. CDK12 induces self-renewal of breast CSCs and in vivo tumor-initiating ability, and also reduces susceptibility to trastuzumab. Furthermore, CDK12 kinase activity inhibition facilitates anticancer efficacy of trastuzumab in HER2(+) tumors, and mice bearing trastuzumab-resistant HER2(+) tumor show sensitivity to an inhibitor of CDK12. Mechanistically, the catalytic activity of CDK12 is required for the expression of genes involved in the activation of ErbB-PI3K-AKT or WNT-signaling cascades. These results suggest that CDK12 is a major oncogenic driver and an actionable target for HER2(+) breast cancer to replace or augment current anti-HER2 therapies.