Abstract
Abstract The p21-activated kinase family of proteins promotes cell survival and plays an important role in cell proliferation, cell cycle regulation and cell shape determination. There are six mammalian PAK proteins which can be subdivided into two groups by sequence homology and mode of activation- Group A Paks consisting of Pak 1, 2 and 3 and Group B Paks consisting of Pak 4, 5 and 6. There is a growing list of evidence that PAK proteins are overexpressed in many cancer types, including colon, lung, and breast cancer. PAK4 is frequently overproduced in breast cancer, including Her2 positive and triple negative breast cancers, while it is expressed at low levels in normal mammary tissue. Our preliminary evidence showed that untransformed mouse mammary epithelial cells have low levels of PAK4 that become elevated when these cells are transformed by Her2 overexpression. Furthermore, PAK4 overexpressed in mammary epithelial cells leads to oncogenic transformation and tumorigenesis in mice. We hypothesize that PAK4 plays an important role in promoting mammary tumorigenesis, and that it can serve as an effective drug target for breast cancer treatment. To test this hypothesis, we have analyzed two orally available PAK4 Allosteric Modulators (PAM; KPT-8752 and KPT-9274), which reduce the steady state PAK4 protein level in cancer cells. We observed that when we treat breast cancer cells with KPT-8752, we severely block the cell growth. KPT-8752, is effective both in Her2 positive and triple negative breast cancer cells. Our results indicate that Pak4 is an important regulator of breast cancer cell growth. Experiments studying the effects of PAMs (KPT8752 and KPT9274) on tumorigenesis in animal models of breast cancer are ongoing. Citation Format: Chetan K. Rane, William Senapedis, Erkan Baloglu, Sharon Shacham, Audrey G. Minden. Inhibition of Pak4 blocks growth of breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4039. doi:10.1158/1538-7445.AM2015-4039
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