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

Autor: William M. Wuest, Anna S. Nikonova, Michelle Borakove, Erica A. Golemis, Alex B. Koval, Vladislav Korobeynikov, Jonathan Chernoff, Elena Shagisultanova, Virginia F. Borges, Ilya G. Serebriiskii, Yayi Feng
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
Cell division
medicine.medical_treatment
Apoptosis
Targeted therapy
Mice
chemistry.chemical_compound
Preclinical Study
Breast cancer
0302 clinical medicine
PAK1
Aurora A
skin and connective tissue diseases
Aurora Kinase A
AURKA
Kinase
Cell Cycle
Cell cycle
Immunohistochemistry
3. Good health
Oncology
030220 oncology & carcinogenesis
Drug Therapy
Combination
Female
Signal Transduction
Cell Survival
Antineoplastic Agents
Breast Neoplasms
Biology
Proto-Oncogene Proteins c-myc
03 medical and health sciences
Cell Line
Tumor
medicine
Animals
Humans
Protein Kinase Inhibitors
Estrogen Receptor alpha
medicine.disease
Xenograft Model Antitumor Assays
Disease Models
Animal
030104 developmental biology
p21-Activated Kinases
chemistry
p21-Activated kinase 1
Alisertib
Cancer research
Estrogen receptor alpha
Zdroj: Breast Cancer Research and Treatment
ISSN: 1573-7217
0167-6806
DOI: 10.1007/s10549-019-05329-2
Popis: 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. Electronic supplementary material The online version of this article (10.1007/s10549-019-05329-2) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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