title: p53 Family Members Regulate Phenotypic Response to Aurora Kinase A Inhibition in Triple-Negative Breast Cancer.
abstract: Triple-negative breast cancer (TNBC) is an aggressive disease with a poor prognosis. Advances in the treatment of TNBC have been hampered by the lack of novel effective targeted therapies. The primary goal of this study was to evaluate the efficacy of targeting Aurora kinase A (AurA), a key regulator of mitosis, in TNBC models. A secondary objective was to determine the role of the p53 family of transcriptional regulators, commonly mutated in TNBC, in determining the phenotypic response to the AurA inhibitor alisertib (MLN8237). Alisertib exhibited potent antiproliferative and proapoptotic activity in a subset of TNBC models. The induction of apoptosis in response to alisertib exposure was dependent on p53 and p73 activity. In the absence of functional p53 or p73, there was a shift in the phenotypic response following alisertib exposure from apoptosis to cellular senescence. In addition, senescence was observed in patient-derived tumor xenografts with acquired resistance to alisertib treatment. AurA inhibitors are a promising class of novel therapeutics in TNBC. The role of p53 and p73 in mediating the phenotypic response to antimitotic agents in TNBC may be harnessed to develop an effective biomarker selection strategy in this difficult to target disease.
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: John J
authors.initials: JJ
authors.lastname: Tentler
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Anastasia A
authors.initials: AA
authors.lastname: Ionkina
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Aik Choon
authors.initials: AC
authors.lastname: Tan
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Newton
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Pitts
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Magdalena J
authors.initials: MJ
authors.lastname: Glogowska
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Peter
authors.initials: P
authors.lastname: Kabos
authors.affiliation: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Sartorius
authors.affiliation: Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, Colorado.
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Sullivan
authors.affiliation: Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, Colorado.
authors.forename: Joaquin M
authors.initials: JM
authors.lastname: Espinosa
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Jennifer.diamond@ucdenver.edu.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Diamond
mesh_terms: D000818:Animals; D017209:Apoptosis; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors; D001381:Azepines / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage* / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001381:Azepines; D004268:DNA-Binding Proteins; C550258:MLN 8237; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C495901:TP53 protein, human; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576917:AURKA protein, human; D064096:Aurora Kinase A