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Korobeynikov V , Borakove M , Feng Y , Wuest WM , Koval AB , Nikonova AS , Serebriiskii I , Chernoff J , Borges VF , Golemis EA , Shagisultanova E
Combined inhibition of Aurora A and p21-activated kinase 1 as a new treatment strategy in breast cancer
Breast Cancer Res Treat. 2019 Sep;177(2) :369-382
PMID: 31254157    PMCID: PMC6661032    URL: https://www.ncbi.nlm.nih.gov/pubmed/31254157
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PURPOSE: The serine-threonine kinases Aurora A (AURKA) and p21-activated kinase 1 (PAK1) are frequently overexpressed in breast tumors, with overexpression promoting aggressive breast cancer phenotypes and poor clinical outcomes. Besides the well-defined roles of these proteins in control of cell division, proliferation, and invasion, both kinases support MAPK kinase pathway activation and can contribute to endocrine resistance by phosphorylating estrogen receptor alpha (ERalpha). PAK1 directly phosphorylates AURKA and its functional partners, suggesting potential value of inhibiting both kinases activity in tumors overexpressing PAK1 and/or AURKA. Here, for the first time, we evaluated the effect of combining the AURKA inhibitor alisertib and the PAK inhibitor FRAX1036 in preclinical models of breast cancer. METHODS: Combination of alisertib and FRAX1036 was evaluated in a panel of 13 human breast tumor cell lines and BT474 xenograft model, with assessment of the cell cycle by FACS, and signaling changes by immunohistochemistry and Western blot. Additionally, we performed in silico analysis to identify markers of response to alisertib and FRAX1036. RESULTS: Pharmacological inhibition of AURKA and PAK1 synergistically decreased survival of multiple tumor cell lines, showing particular effectiveness in luminal and HER2-enriched models, and inhibited growth and ERalpha-driven signaling in a BT474 xenograft model. In silico analysis suggested cell lines with dependence on AURKA are most likely to be sensitive to PAK1 inhibition. CONCLUSION: Dual targeting of AURKA and PAK1 may be a promising therapeutic strategy for treatment of breast cancer, with a particular effectiveness in luminal and HER2-enriched tumor subtypes.
1573-7217 Korobeynikov, Vladislav Borakove, Michelle Feng, Yayi Wuest, William M Koval, Alex B Nikonova, Anna S Serebriiskii, Ilya Chernoff, Jonathan Borges, Virginia F Golemis, Erica A Shagisultanova, Elena ORCID: http://orcid.org/0000-0003-1389-1116 Seed Award/American Cancer Society R01 CA142928/National Institutes of Health R01 DK108195/National Institutes of Health Institute core grant P30 CA06927 to Fox Chase Cancer Center/National Cancer Institute not applicable/Robert F. and Patricia Young Connor Endowed Chair in Young Women's Breast Cancer Research Journal Article Netherlands Breast Cancer Res Treat. 2019 Jun 28. pii: 10.1007/s10549-019-05329-2. doi: 10.1007/s10549-019-05329-2.