TY - JOUR
T1 - P53 family members regulate phenotypic response to Aurora kinase a inhibition in Triple-negative breast cancer
AU - Tentler, John J.
AU - Ionkina, Anastasia A.
AU - Tan, Aik Choon
AU - Newton, Timothy P.
AU - Pitts, Todd M.
AU - Glogowska, Magdalena J.
AU - Kabos, Peter
AU - Sartorius, Carol A.
AU - Sullivan, Kelly D.
AU - Espinosa, Joaquin M.
AU - Eckhardt, S. Gail
AU - Diamond, Jennifer R.
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84942118394&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-14-0538-T
DO - 10.1158/1535-7163.MCT-14-0538-T
M3 - Article
C2 - 25758253
AN - SCOPUS:84942118394
SN - 1535-7163
VL - 14
SP - 1117
EP - 1129
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 5
ER -
