新老药物联合可治疗三阴性乳腺癌
由于三阴性乳腺癌缺乏可靶向治疗的雌激素受体、孕激素受体、HER2，故为目前临床最难治疗的乳腺癌亚型。细胞周期蛋白依赖型激酶（CDK）4/6抑制剂新药（辉瑞的哌柏西利、诺华的瑞波西利、礼来的阿贝西利）通过减少视网膜母细胞瘤蛋白（Rb）磷酸化可以阻断肿瘤细胞分裂周期，已被证实对激素受体阳性HER2阴性乳腺癌效果良好，而表皮生长因子受体（EGFR）抑制剂老药拉帕替尼地龙胶囊对路由器怎么改密码HER2阳性乳腺癌志愿者在行动有效，但是均对梭罗简介三阴性乳腺癌效果不佳。垃圾分类心得
2019年6月28日，英国《自然》旗下《自然通讯》在线发表美国印地安纳南湾天主教圣母大学、印第安纳大学医学院西蒙癌症中心的研究报告，发现诱发三阴性乳腺癌容易受到细胞周期抑制作用的新策略。
该研究通过细胞质定位，发现包含细胞死亡效应结构的DNA结合蛋白质（DEDD）过度表达于超过60%的三阴性乳腺癌，可以不依靠促细胞有丝分裂原，直接驱动细胞有丝分裂周期由DNA合成前期（G1）进入DNA合成期（S）。提高细胞质DEDD水平，通过与热休克71kDa蛋白8（HSC70）日近黄昏打一地名>斯苗儿相互作用，可以增强细胞周期蛋白D1的表达。同时，DEDD与Rb相互作用并且促进其蛋白酶体所致降解。DEDD过度表达可以使三阴性乳腺癌容易受到细胞周期抑制
作用。由于三阴性乳腺癌的Rb缺失率高，故CDK4/6抑制剂临床研究通常不考虑入组三阴性乳腺癌患者。有趣的是，该研究表明，无论Rb状态如何，DEDD过度表达的三阴性乳腺癌在体外和体内都表现出容易受到DEDD依赖型CDK4/6抑制剂和EGFR抑制剂拉帕替尼联合治疗的影响。
因此，该研究结果表明，CDK4/6抑制剂新药和EGFR抑制剂老药的联合方案，有望被临床用于三阴性乳腺癌患者的治疗。
Nat Commun. 2019 Jun 28. [Epub ahead of print]
Death effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer.看押
Yingjia Ni, Keon R. Schmidt, Barnes A. Werner, Jenna K. Koenig, Ian H. Guldner, Patricia M. Schnepp, Xuejuan Tan, Lan Jiang, Misha Host, Longhua Sun, Erin N. Howe, Junmin Wu, Laurie E. Littlepage, Harikrishna Nakshatri, Siyuan Zhang.
University of Notre Dame, Notre Dame, IN, USA; University of Notre Dame, South Bend,
IN, USA; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA; Indiana University School of Medicine, Indianapolis, IN, USA.
Lacking targetable molecular drivers, triple-negative breast cancer (TNBC) is the most clinically challenging subtype of breast cancer. In this study, we reveal that Death Effector Domain-containing DNA-binding protein (DEDD), which is overexpresd in>60% of TNBCs, drives a mitogen-independent G1/S cell cycle transition through cytoplasm localization. The gain of cytosolic DEDD enhances cyclin D1 expression by interacting with heat shock 71kDa protein 8 (HSC70). Concurrently, DEDD interacts with Rb family proteins and promotes their proteasome-mediated degradation. DEDD overexpression renders TNBCs vulnerable to cell cycle inhibition. Patients with TNBC have been excluded from CDK 4/6 inhibitor clinical trials due to the perceived high frequency of Rb-loss in TNBCs. Interestingly, our study demonstrated that, irrespective of Rb status, TNBCs with DEDD overexpression exhibit a DEDD-dependent vulnerability to combinatorial treatment with CDK4/6 inhibitor and EGFR inhibitor in vitro and in vivo. Thus, our study provided a rationale for the clinical application of CDK4/6 inhibitor combin
atorial regimens for patients with TNBC.
DOI: 10.1038/s41467-019-10743-7
