Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ, 08854, USA.
Karyopharm Therapeutics, Inc., 85 Wells Avenue, Newton, MA, 02459, USA.
Sci Rep. 2017 Feb 15;7:42555. doi: 10.1038/srep42555.
Breast cancer is a heterogeneous disease consisting of several subtypes. Among these subtypes, triple negative breast cancer is particularly difficult to treat. This is due to a lack of understanding of the mechanisms behind the disease, and consequently a lack of druggable targets. PAK4 plays critical roles in cell survival, proliferation, and morphology. PAK4 protein levels are high in breast cancer cells and breast tumors, and the gene is often amplified in basal like breast cancers, which are frequently triple negative. PAK4 is also overexpressed in other types of cancer, making it a promising drug target. However, its inhibition is complicated by the fact that PAK4 has both kinase-dependent and -independent functions. Here we investigate a new clinical compound KPT-9274, which has been shown to inhibit PAK4 and NAMPT. We find that KPT-9274 (and its analog, KPT-8752) can reduce the steady state level of PAK4 protein in triple negative breast cancer cells. These compounds also block the growth of the breast cancer cells in vitro, and stimulate apoptosis. Most importantly, oral administration of KPT-9274 reduces tumorigenesis in mouse models of human triple negative breast cancer. Our results indicate that KPT-9274 is a novel therapeutic option for triple negative breast cancer therapy.
乳腺癌是一种具有多种亚型的异质性疾病。在这些亚型中，三阴性乳腺癌特别难以治疗。这是由于对疾病背后的机制缺乏了解，因此缺乏可成药的靶点。PAK4 在细胞存活、增殖和形态中发挥关键作用。PAK4 蛋白水平在乳腺癌细胞和乳腺癌肿瘤中较高，并且该基因在基底样乳腺癌中经常扩增，而基底样乳腺癌通常是三阴性的。PAK4 在其他类型的癌症中也过表达，使其成为一个有前途的药物靶点。然而，其抑制作用很复杂，因为 PAK4 具有激酶依赖性和非依赖性功能。在这里，我们研究了一种新的临床化合物 KPT-9274，它已被证明可以抑制 PAK4 和 NAMPT。我们发现 KPT-9274（及其类似物 KPT-8752）可以降低三阴性乳腺癌细胞中 PAK4 蛋白的稳态水平。这些化合物还可以阻断乳腺癌细胞在体外的生长，并刺激细胞凋亡。最重要的是，口服 KPT-9274 可减少人三阴性乳腺癌小鼠模型中的肿瘤发生。我们的结果表明，KPT-9274 是三阴性乳腺癌治疗的一种新的治疗选择。
