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

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

doi:10.1007/s10549-019-05329-2

Abstract

PurposeThe 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.MethodsCombination 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.ResultsPharmacological 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.ConclusionDual 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.

Highlights

We evaluated the effect of dual inhibition of AURKA and p21-activated kinase 1 (PAK1) on the proliferation of 5 luminal (MCF7, ZR75, T47D, BT474, MDA-MB-361), 4 hormone receptor negative (HR-) human epidermal growth factor receptor 2 positive (HER2 +) (HCC1954, HCC1419, HCC1569, SKBR3), and 4 triple negative (TNBC) (MDA-MB-157, MDA-MB-468, MDA-MB-231, HCC1806) breast cancer cell lines (Fig. 1, S1)
Our results indicate that combined inhibition of AURKA and PAK1 is of potential value for the treatment of breast cancer, with greatest efficacy seen in luminal HR + and HER2 + subtypes in vitro
This could be explained by the interaction of AURKA and PAK1 with ERα, and with HER2 [4, 18]

Summary

Introduction

The serine-threonine kinases Aurora A (AURKA) and p21-activated kinase 1 (PAK1) are frequently overexpressed in breast tumors and associated with aggressive tumor. ◂Fig. 1 Cell viability in breast cancer cell lines treated with FRAX1036 and alisertib. A Cell lines with demonstrated synergy of alisertib/FRAX1036 combination; drug concentrations that showed synergy are marked with asterisks; ChowTalalay analysis of synergy is presented below each cell viability graph (CI—combination index; CI < 1 indicate synergy, CI = 1 additive effect; CI > 1 antagonistic effect). In interphase, overexpressed AURKA stabilizes C-MYC [9] and stimulates the PI3K/AKT/mTOR pathway, promoting chemotherapeutic resistance [10]. Like AURKA, PAK1 stimulates multiple prooncogenic pathways, including AKT, C-MYC, and β-catenin [11, 12], promoting proliferation, motility, and invasion [11, 13]. AURKA and PAK1 function within overlapping but distinct signaling pathways, PAK1 is capable of AURKA activation: both directly, by phosphorylating serine S342 and threonine T288 in the activation loop [15], and indirectly, by phosphorylation of the AURKA-activating protein partners LIMK1 and ARPC1b [15,16,17]

Methods

Results

Conclusion