Development of a RSK Inhibitor as a Novel Therapy for Triple-Negative Breast Cancer.
Development of a RSK Inhibitor as a Novel Therapy for Triple-Negative Breast Cancer.
复制标题
DOI：
10.1158/1535-7163.mct-16-0106
复制
发表时间：
2016-11
影响因子：
5.7
通讯作者：
Lannigan DA
中科院分区：
文献类型：
--
作者：
Ludwik KA;Campbell JP;Li M;Li Y;Sandusky ZM;Pasic L;Sowder ME;Brenin DR;Pietenpol JA;O'Doherty GA;Lannigan DA
转移性乳腺癌是一种无法治愈的疾病，识别新的治疗机会至关重要。三阴性乳腺癌 (TNBC) 经常发生转移，并且在 TNBC 中发现高水平的活化 RSK（下游 MEK-ERK1/2 效应子）。我们通过直接药理学和遗传抑制 RSK1/2 证明，这些激酶有助于体内 TNBC 转移过程。激酶分析表明，RSK1 和 RSK2 是新抑制剂的主要靶标激酶，该抑制剂基于天然产物 SL0101。沉默 RSK1 和 RSK2 消除了类似物进一步抑制 TNBC 细胞系存活或增殖的能力，这一观察结果为选择性提供了进一步的证据。在体内，新衍生物在减少转移灶的形成方面与 FDA 批准的 MEK 抑制剂曲美替尼 (Trametinib) 一样有效。重要的是，抑制 RSK1/2 不会导致 AKT 激活，而 AKT 已知会限制 MEK 抑制剂在临床上的功效。我们的结果表明，RSK 是 TNBC 转移计划的主要贡献者，并为新型 SL0101 类似物的体内功效提供临床前概念验证。
Metastatic breast cancer is an incurable disease and identification of novel therapeutic opportunities is vital. Triple negative breast cancer (TNBC) frequently metastasizes and high levels of activated RSK, a downstream MEK-ERK1/2 effector, are found in TNBC. We demonstrate using direct pharmacological and genetic inhibition of RSK1/2 that these kinases contribute to the TNBC metastatic process in vivo. Kinase profiling demonstrated that RSK1 and RSK2 are the predominant kinases targeted by the new inhibitor, which is based on the natural product, SL0101. Further evidence for selectivity was provided by the observations that silencing RSK1 and RSK2 eliminated the ability of the analogue to further inhibit survival or proliferation of a TNBC cell line. In vivo, the new derivative was as effective as the FDA-approved MEK inhibitor, trametinib, in reducing the establishment of metastatic foci. Importantly, inhibition of RSK1/2 did not result in activation of AKT, which is known to limit the efficacy of MEK inhibitors in the clinic. Our results demonstrate that RSK is a major contributor to the TNBC metastatic program and provide preclinical proof-of-concept for the efficacy of the novel SL0101 analogue in vivo.