Combination of Eribulin and Aurora A Inhibitor MLN8237 Prevents Metastatic Colonization and Induces Cytotoxic Autophagy in Breast Cancer.

Autor:	Kozyreva VK; West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia., Kiseleva AA; Department of Biochemistry, West Virginia University School of Medicine, Morgantown, West Virginia. Department of Biochemistry and Biotechnology, Kazan Federal University, Kazan, Tatarstan., Ice RJ; West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia., Jones BC; Department of Biochemistry, West Virginia University School of Medicine, Morgantown, West Virginia., Loskutov YV; West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia., Matalkah F; West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia., Smolkin MB; Department of Pathology, West Virginia University School of Medicine, Morgantown, West Virginia., Marinak K; West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia., Livengood RH; Department of Pathology, West Virginia University School of Medicine, Morgantown, West Virginia., Salkeni MA; West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia. Department of Medicine, West Virginia University School of Medicine, Morgantown, West Virginia., Wen S; West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia. Department of Biostatistics, West Virginia University School of Medicine, Morgantown, West Virginia., Hazard HW; West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia. Department of Surgery, West Virginia University School of Medicine, Morgantown, West Virginia., Layne GP; West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia. Department of Radiology, West Virginia University School of Medicine, Morgantown, West Virginia., Walsh CM; Protea Biosciences, Inc., Morgantown, West Virginia., Cantrell PS; Protea Biosciences, Inc., Morgantown, West Virginia., Kilby GW; Protea Biosciences, Inc., Morgantown, West Virginia., Mahavadi S; INBRE Program, West Virginia University School of Medicine, Morgantown, West Virginia., Shah N; West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia., Pugacheva EN; West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia. Department of Biochemistry, West Virginia University School of Medicine, Morgantown, West Virginia. epugacheva@hsc.wvu.edu.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2016 Aug; Vol. 15 (8), pp. 1809-22. Date of Electronic Publication: 2016 May 27.
DOI:	10.1158/1535-7163.MCT-15-0688
Abstrakt:	Recent findings suggest that the inhibition of Aurora A (AURKA) kinase may offer a novel treatment strategy against metastatic cancers. In the current study, we determined the effects of AURKA inhibition by the small molecule inhibitor MLN8237 both as a monotherapy and in combination with the microtubule-targeting drug eribulin on different stages of metastasis in triple-negative breast cancer (TNBC) and defined the potential mechanism of its action. MLN8237 as a single agent and in combination with eribulin affected multiple steps in the metastatic process, including migration, attachment, and proliferation in distant organs, resulting in suppression of metastatic colonization and recurrence of cancer. Eribulin application induces accumulation of active AURKA in TNBC cells, providing foundation for the combination therapy. Mechanistically, AURKA inhibition induces cytotoxic autophagy via activation of the LC3B/p62 axis and inhibition of pAKT, leading to eradication of metastases, but has no effect on growth of mammary tumor. Combination of MLN8237 with eribulin leads to a synergistic increase in apoptosis in mammary tumors, as well as cytotoxic autophagy in metastases. These preclinical data provide a new understanding of the mechanisms by which MLN8237 mediates its antimetastatic effects and advocates for its combination with eribulin in future clinical trials for metastatic breast cancer and early-stage solid tumors. Mol Cancer Ther; 15(8); 1809-22. ©2016 AACR. (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
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