Abstract

Triple-negative breast cancer (TNBC) is a subtype associated with poor prognosis and for which there are limited therapeutic options. The purpose of this study was to evaluate the efficacy of ENMD-2076 in p53-mutated TNBC patient-derived xenograft (PDX) models and describe patterns of terminal cell fate in models demonstrating sensitivity, intrinsic resistance, and acquired resistance to ENMD-2076. p53-mutated, TNBC PDX models were treated with ENMD-2076 and evaluated for mechanisms of sensitivity or resistance to treatment. Correlative tissue testing was performed on tumor tissue to assess for markers of proliferation, apoptosis, senescence, and pathways of resistance after treatment and at the time of acquired resistance. Sensitivity to ENMD-2076 200 mg/kg daily was associated with induction of apoptosis while models exhibiting intrinsic or acquired resistance to treatment presented with a senescent phenotype. Response to ENMD-2076 was accompanied by an increase in p53 and p73 levels, even within the background of mutant p53. Treatment with ENMD-2076 resulted in a decrease in pAurA and an increase in pHH3. We observed a TNBC subtype switch from the luminal androgen receptor to the basal-like subtype at acquired resistance. ENMD-2076 has antitumor activity in preclinical models of p53-mutated TNBC. Increased levels of p53 and p73 correlated with sensitivity whereas senescence was associated with resistance to ENMD-2076. The novel finding of a TNBC subtype switch at time of acquired resistance may provide mechanistic insights into the biologic effects of selective pressure of anticancer treatments on TNBC. ENMD-2076 is currently being evaluated in a Phase 2 clinical trial in patients with metastatic, previously treated TNBC where these biologic correlates can be further explored.

Highlights

  • Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by a lack of estrogen and progesterone receptor expression and HER2 amplification [1,2,3]

  • The antitumor activity of ENMD-2076 was evaluated in vivo against three TNBC patient-derived xenograft (PDX) models

  • In order to understand the mechanism of tumor growth inhibition and decreased cellular proliferation observed with ENMD2076 treatment in vivo, we investigated known mediators of apoptosis

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Summary

Introduction

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by a lack of estrogen and progesterone receptor expression and HER2 amplification [1,2,3]. Despite a relatively high initial response rate to chemotherapy, patients with TNBC face a higher risk of cancer recurrence and subsequent cancer-related death [4, 5]. The treatment of metastatic TNBC remains sequential lines of chemotherapy; most tumors develop acquired resistance to treatment quite rapidly [6]. The development of targeted anticancer therapies for TNBC remains an unmet clinical need to decrease TNBC-related morbidity and mortality [7]. Aurora kinase A (AurA) is a serine/threonine kinase integral to mitotic cell division [8, 9]. Aurora kinase inhibitors (AKIs) are active against preclinical TNBC models where exposure leads to a G2/M cell cycle arrest followed by aneuploidy and mitotic catastrophe [13,14,15]

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