CUDC-101, a Multitargeted Inhibitor of Histone Deacetylase, Epidermal Growth Factor Receptor, and Human Epidermal Growth Factor Receptor 2, Exerts Potent Anticancer Activity
CUDC-101, a Multitargeted Inhibitor of Histone Deacetylase, Epidermal Growth Factor Receptor, and Human Epidermal Growth Factor Receptor 2, Exerts Potent Anticancer Activity
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DOI：
10.1158/0008-5472.can-09-3360
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发表时间：
2010-05-01
期刊：
影响因子：
11.2
通讯作者：
Qian, Changgeng
中科院分区：
文献类型：
--
作者：
Lai, Cheng-Jung;Bao, Rudi;Qian, Changgeng
受体酪氨酸激酶抑制剂最近已成为多种癌症的重要治疗剂。然而，由于肿瘤的异质性和动态性，这些药物的有效性往往受到不良反应率和获得性耐药性的阻碍。为了克服这些限制，我们创造了一种新型的小分子CUDC-101，它同时抑制癌细胞中的组蛋白脱乙酰酶和受体激酶表皮生长因子受体（EGFR）和人表皮生长因子受体2（HER2）。由于其整合的组蛋白去乙酰化酶抑制作用，CUDC-101协同阻断EGFR/HER2信号通路的关键调节因子，也减弱了多种代偿通路，如AKT、HER3和MET，使癌细胞能够逃避常规EGFR/HER2抑制剂的作用。CUDC-101对培养和植入的肿瘤细胞显示出有效的抗增殖和促凋亡活性，这些肿瘤细胞对几种批准的单靶向药物敏感或耐药。我们的研究结果表明，CUDC-101有潜力显着改善单靶点药物无法控制的异质性和耐药性肿瘤的治疗。此外，它们提供了一个框架来创建同时拮抗多种生物化学上不同的致癌靶点的单个小分子，这表明了超越传统的单靶点癌症治疗的一般范式。Cancer Res; 70（9）; 3647 - 56. (C)2010年AACR。
Receptor tyrosine kinase inhibitors have recently become important therapeutics for a variety of cancers. However, due to the heterogeneous and dynamic nature of tumors, the effectiveness of these agents is often hindered by poor response rates and acquired drug resistance. To overcome these limitations, we created a novel small molecule, CUDC-101, which simultaneously inhibits histone deacetylase and the receptor kinases epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) in cancer cells. Because of its integrated histone deacetylase inhibition, CUDC-101 synergistically blocked key regulators of EGFR/HER2 signaling pathways, also attenuating multiple compensatory pathways, such as AKT, HER3, and MET, which enable cancer cells to escape the effects of conventional EGFR/HER2 inhibitors. CUDC-101 displayed potent antiproliferative and proapoptotic activities against cultured and implanted tumor cells that are sensitive or resistant to several approved single-targeted drugs. Our results show that CUDC-101 has the potential to dramatically improve the treatment of heterogeneous and drug-resistant tumors that cannot be controlled with single-target agents. Further, they provide a framework to create individual small molecules that simultaneously antagonize multiple biochemically distinct oncogenic targets, suggesting a general paradigm to surpass conventional, single-target cancer therapeutics. Cancer Res; 70(9); 3647-56. (C) 2010 AACR.