P53 family members regulate phenotypic response to Aurora kinase a inhibition in Triple-negative breast cancer

John J. Tentler, Anastasia A. Ionkina, Aik Choon Tan, Timothy P. Newton, Todd M. Pitts, Magdalena J. Glogowska, Peter Kabos, Carol A. Sartorius, Kelly D. Sullivan, Joaquin M. Espinosa, S. Gail Eckhardt, Jennifer R. Diamond

    Research output: Contribution to journalArticlepeer-review

    39 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)1117-1129
    Number of pages13
    JournalMolecular cancer therapeutics
    Volume14
    Issue number5
    DOIs
    Publication statusPublished - 2015 May 1

    Bibliographical note

    Publisher Copyright:
    © 2015 American Association for Cancer Research.

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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