Abstract
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.
Highlights
Frequently triple negative, DNA analysis revealed that the chromosomal region containing the gene for PAK4 was frequently amplified[12]
Our previous research has shown that when PAK4 is overexpressed in non-transformed immortalized mouse mammary epithelial cells, it results in improper formation of spherical acini in 3D culture
The PAK4-expressing immortalized mouse mammary epithelial cells (iMMECs) formed tumors when implanted into the mammary fat pads of mice[6], providing strong evidence that overexpression of the wild-type PAK4 protein is sufficient to lead to mammary tumorigenesis in mice
Summary
Frequently triple negative, DNA analysis revealed that the chromosomal region containing the gene for PAK4 was frequently amplified[12]. We found that PAK4 overexpression led to oncogenic transformation in mouse mammary epithelial cells while blocking PAK4 with siRNA inhibited tumor formation of a human breast cancer cell line[6,13] These data suggest a significant role for PAK4 in breast cancer etiology and make it a potential therapeutic target. KPT-9274, along with the structural analog KPT-8752 (both developed by Karyopharm Therapeutics), function differently from other PAK4 inhibitors in that they reduce the steady state level of PAK4 protein in cells This reduction is important because PAK4, like other PAK family members, has been found to have several kinase-independent functions[10,11,38,39,40,41]. Inhibitors that can reduce PAK4 protein and not just the kinase activity are needed in order to more efficiently block PAK4 in cancer
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