title: Combination of Eribulin and Aurora A Inhibitor MLN8237 Prevents Metastatic Colonization and Induces Cytotoxic Autophagy in Breast Cancer.
abstract: 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.
authors.affiliation: West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Varvara K
authors.initials: VK
authors.lastname: Kozyreva
authors.affiliation: Department of Biochemistry, West Virginia University School of Medicine, Morgantown, West Virginia. Department of Biochemistry and Biotechnology, Kazan Federal University, Kazan, Tatarstan.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Kiseleva
authors.affiliation: West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Ice
authors.affiliation: Department of Biochemistry, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Brandon C
authors.initials: BC
authors.lastname: Jones
authors.affiliation: West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Yuriy V
authors.initials: YV
authors.lastname: Loskutov
authors.affiliation: West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Fatimah
authors.initials: F
authors.lastname: Matalkah
authors.affiliation: Department of Pathology, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Smolkin
authors.affiliation: West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Kristina
authors.initials: K
authors.lastname: Marinak
authors.affiliation: Department of Pathology, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Ryan H
authors.initials: RH
authors.lastname: Livengood
authors.affiliation: 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.
authors.forename: Mohamad A
authors.initials: MA
authors.lastname: Salkeni
authors.affiliation: 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.
authors.forename: Sijin
authors.initials: S
authors.lastname: Wen
authors.affiliation: 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.
authors.forename: Hannah W
authors.initials: HW
authors.lastname: Hazard
authors.affiliation: 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.
authors.forename: Ginger P
authors.initials: GP
authors.lastname: Layne
authors.affiliation: Protea Biosciences, Inc., Morgantown, West Virginia.
authors.forename: Callee M
authors.initials: CM
authors.lastname: Walsh
authors.affiliation: Protea Biosciences, Inc., Morgantown, West Virginia.
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Cantrell
authors.affiliation: Protea Biosciences, Inc., Morgantown, West Virginia.
authors.forename: Greg W
authors.initials: GW
authors.lastname: Kilby
authors.affiliation: INBRE Program, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Sricharan
authors.initials: S
authors.lastname: Mahavadi
authors.affiliation: West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Neal
authors.initials: N
authors.lastname: Shah
authors.affiliation: 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.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Pugacheva
mesh_terms: D000818:Animals; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors*; D001343:Autophagy / Q000187:drug effects*; D001381:Azepines / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D007659:Ketones / Q000494:pharmacology*; D008297:Male; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000095662:Polyether Polyketides
chemical_list: D064096:Aurora Kinase A; D001381:Azepines; D005663:Furans; D007659:Ketones; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C550258:MLN 8237; C490954:eribulin; D000095662:Polyether Polyketides