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

• Type of Material: Article
• Authors: Vladislav Korobeynikov, Columbia University College of Physicians and Surgeons; Michelle Borakove, University of Colorado Denver; Yayi Feng, Fox Chase Cancer Center; William Wuest, Emory University; Alex B. Koval, Temple University; Anna S. Nikonova, Fox Chase Cancer Center; Ilya Serebriiskii, Fox Chase Cancer Center; Jonathan Chernoff, Fox Chase Cancer Center; Virginia F. Borges, University of Colorado Denver; Erica A. Golemis, Fox Chase Cancer Center; Elena Shagisultanova, University of Colorado Denver
• Language: English
• Date: 2019-09-01
• Publisher: Springer (part of Springer Nature): Springer Open Choice Hybrid Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2019, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1007/s10549-019-05329-2
• Title of Journal or Parent Work: Breast Cancer Research and Treatment
• ISSN: 0167-6806
• Volume: 177
• Issue: 2
• Start Page: 369
• End Page: 382
• Grant/Funding Information: The study and authors were funded by American Cancer Society Seed Award (to ES); Robert F. and Patricia Young Connor Endowed Chair in Young Women’s Breast Cancer Research Award (to VFB); National Institute of Health R01 CA142928 (to JC); National Institute of Health R01 DK108195 (to EAG); a subsidy of the Russian Government to support the Program of Competitive Growth of Kazan Federal University (to IGS); and National Cancer Institute Core Grant P30 CA06927 (to Fox Chase Cancer Center, FCCC).
• Keywords: Science & Technology; Oncology; Targeted therapy; PHASE-I; KINASE; Breast cancer; Life Sciences & Biomedicine; PAK1; OVARIAN; C-MYC; ACTIVATION; p21-Activated kinase 1; TO-MESENCHYMAL TRANSITION; Aurora A; MLN8237; CELLS; ALISERTIB; AURKA
• Research Categories: Health Sciences, Oncology; Chemistry, General

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.