Definition of PKC-α, CDK6, and MET as therapeutic targets in triple-negative breast cancer.
Definition of PKC-α, CDK6, and MET as therapeutic targets in triple-negative breast cancer.
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DOI：
10.1158/0008-5472.can-14-0584
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发表时间：
2014-09-01
期刊：
影响因子：
11.2
通讯作者：
Hung MC
中科院分区：
文献类型：
--
作者：
Hsu YH;Yao J;Chan LC;Wu TJ;Hsu JL;Fang YF;Wei Y;Wu Y;Huang WC;Liu CL;Chang YC;Wang MY;Li CW;Shen J;Chen MK;Sahin AA;Sood A;Mills GB;Yu D;Hortobagyi GN;Hung MC
三阴性乳腺癌（TNBC）是一种高度异质性和复发性的乳腺癌亚型，缺乏有效的靶向治疗。为了确定候选治疗靶点，我们利用患者生存数据集分析了 TNBC 和乳腺肿瘤起始细胞的全局基因表达。发现八种 TNBC 相关激酶在具有干细胞样特性的 TNBC 细胞中过度表达。其中，PKC-α、MET 和 CDK6 的表达与较差的生存结果相关。在共表达这三种激酶中的两种的情况下，存活率低于仅表达这些激酶中的一种的情况。在功能测试中，针对这三种激酶的两种药物组合以协同方式抑制 TNBC 细胞增殖和致瘤潜力。 PKC-α-MET 抑制剂的组合也在体内以协同方式减弱肿瘤生长。我们的研究结果定义了对 TNBC 生长至关重要的三种激酶，并为它们作为 TNBC 有效治疗靶点的候选资格提供了临床前基本原理。
Triple-negative breast cancer (TNBC) is a highly heterogeneous and recurrent subtype of breast cancer that lacks an effective targeted therapy. To identify candidate therapeutic targets, we profiled global gene expression in TNBC and breast tumor-initiating cells with a patient survival dataset. Eight TNBC-related kinases were found to be overexpressed in TNBC cells with stem-like properties. Among them, expression of PKC-α, MET and CDK6 correlated with poorer survival outcomes. In cases co-expressing two of these three kinases, survival rates were lower than in cases where only one of these kinases was expressed. In functional tests, two-drug combinations targeting these three kinases inhibited TNBC cell proliferation and tumorigenic potential in a cooperative manner. A combination of PKC-α−MET inhibitors also attenuated tumor growth in a cooperative manner in vivo. Our findings define three kinases critical for TNBC growth and offer a preclinical rationale for their candidacy as effective therapeutic targets in treating TNBC.