Estrogen receptor coregulator binding modulators (ERXs) effectively target estrogen receptor positive human breast cancers
Estrogen receptor coregulator binding modulators (ERXs) effectively target estrogen receptor positive human breast cancers
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DOI：
10.7554/elife.26857
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发表时间：
2017-08-08
期刊：
影响因子：
7.7
通讯作者：
Vadlamudi, Ratna K.
中科院分区：
文献类型：
--
作者：
Raj, Ganesh V.;Sareddy, Gangadhara Reddy;Vadlamudi, Ratna K.
大多数人乳腺癌是雌激素受体α（ER）阳性。虽然抗雌激素/芳香酶抑制剂最初是有效的，但通常会对这些药物产生耐药性。耐药肿瘤通常通过与关键致癌辅调节蛋白相互作用保留ER信号传导。为了解决这些耐药机制，我们开发了一种新的ER辅调节因子结合调节剂ERX-11。ERX-11直接与ER相互作用，并阻断一部分辅调节因子与天然和突变形式的ER之间的相互作用。ERX-11有效阻断ER介导的致癌信号传导，并对治疗敏感和治疗耐药的人乳腺癌细胞具有强效抗增殖活性。ERX-11是口服生物可利用的，在小鼠异种移植物和患者来源的乳腺肿瘤外植体模型中没有明显的毒性和有效活性迹象。这种一流的药物，其破坏关键蛋白质-蛋白质相互作用的新作用机制，克服了目前治疗的局限性，并可能在临床上转化为治疗敏感和治疗耐药的乳腺癌患者。
The majority of human breast cancer is estrogen receptor alpha (ER) positive. While anti-estrogens/aromatase inhibitors are initially effective, resistance to these drugs commonly develops. Therapy-resistant tumors often retain ER signaling, via interaction with critical oncogenic coregulator proteins. To address these mechanisms of resistance, we have developed a novel ER coregulator binding modulator, ERX-11. ERX-11 interacts directly with ER and blocks the interaction between a subset of coregulators with both native and mutant forms of ER. ERX-11 effectively blocks ER-mediated oncogenic signaling and has potent anti-proliferative activity against therapy-sensitive and therapy-resistant human breast cancer cells. ERX-11 is orally bioavailable, with no overt signs of toxicity and potent activity in both murine xenograft and patient-derived breast tumor explant models. This first-in-class agent, with its novel mechanism of action of disrupting critical protein-protein interactions, overcomes the limitations of current therapies and may be clinically translatable for patients with therapy-sensitive and therapy-resistant breast cancers.