Iorns Elizabeth, Lord Christopher J, Ashworth Alan
The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London SW36JB, UK.
Biochem J. 2009 Jan 1;417(1):361-70. doi: 10.1042/BJ20081682.
Tamoxifen is the most commonly used drug to treat breast cancer and acts by blocking ERalpha (oestrogen receptor alpha) signalling. Although highly effective, its usefulness is limited by the development of resistance. Given this, strategies that limit resistance by sensitizing cells to tamoxifen may be of use in the clinic. To gain insight into how this might be achieved, we used chemical and genetic screens to identify targets and small-molecule inhibitors that cause tamoxifen sensitization. A high-throughput genetic screen, using an RNA interference library targeting 779 kinases and related proteins, identified the PDK1 (phosphoinositide-dependent kinase 1) signalling pathway as a strong determinant of sensitivity to multiple ERalpha antagonists, including tamoxifen. A chemical screen using existing drugs and known kinase inhibitors also identified inhibitors of the PDK1 pathway, including triciribine and tetrandrine. Aside from identifying novel agents and targets for tamoxifen sensitization, this approach also provides evidence that performing chemical and genetic screens in parallel may be useful.
他莫昔芬是治疗乳腺癌最常用的药物，其作用机制是阻断雌激素受体α（ERα）信号传导。尽管它非常有效，但其疗效因耐药性的产生而受到限制。鉴于此，通过使细胞对他莫昔芬敏感来限制耐药性的策略可能在临床上有用。为了深入了解如何实现这一点，我们使用化学和基因筛选来鉴定导致他莫昔芬敏感化的靶点和小分子抑制剂。一项高通量基因筛选，使用针对779种激酶和相关蛋白的RNA干扰文库，确定磷脂酰肌醇依赖性激酶1（PDK1）信号通路是对包括他莫昔芬在内的多种ERα拮抗剂敏感性的一个重要决定因素。一项使用现有药物和已知激酶抑制剂的化学筛选也鉴定出了PDK1通路的抑制剂，包括三氮唑核苷和粉防己碱。除了鉴定用于他莫昔芬敏感化的新型药物和靶点外，这种方法还提供了证据表明并行进行化学和基因筛选可能是有用的。
