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Open Access 01-09-2019 | Breast Cancer | Preclinical study

Combined inhibition of Aurora A and p21-activated kinase 1 as a new treatment strategy in breast cancer

Authors: Vladislav Korobeynikov, Michelle Borakove, Yayi Feng, William M. Wuest, Alex B. Koval, Anna S. Nikonova, Ilya Serebriiskii, Jonathan Chernoff, Virginia F. Borges, Erica A. Golemis, Elena Shagisultanova

Published in: Breast Cancer Research and Treatment | Issue 2/2019

Abstract

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 (ERα). 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 ERα-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.

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Title: Combined inhibition of Aurora A and p21-activated kinase 1 as a new treatment strategy in breast cancer
Authors: Vladislav Korobeynikov
Michelle Borakove
Yayi Feng
William M. Wuest
Alex B. Koval
Anna S. Nikonova
Ilya Serebriiskii
Jonathan Chernoff
Virginia F. Borges
Erica A. Golemis
Elena Shagisultanova
Publication date: 01-09-2019
Publisher: Springer US
Keywords: Breast Cancer
Breast Cancer
Published in: Breast Cancer Research and Treatment / Issue 2/2019
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-019-05329-2

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Abstract

Purpose

Methods

Results

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