A novel orally bioavailable compound KPT-9274 inhibits PAK4, and blocks triple negative breast cancer tumor growth

• DOI: 10.1038/srep42555
• Publication Date: 2017-02-15T10:16:00Z
• Authors: Chetan Rane; William Senapedis; Erkan Baloglu; Yosef Landesman; Marsha Crochiere; Soumyasri Das-Gupta; Audrey Minden
• Keywords: Acrylamides; 0303 health sciences; Cell Survival; Aminopyridines; Antineoplastic Agents; Apoptosis; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays; Article; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; Cell Transformation, Neoplastic; p21-Activated Kinases; Cell Line, Tumor; Animals; Humans; Female; Phosphorylation; Cell Proliferation

AbstractBreast 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.