Abstract
BackgroundBased on promising phase II data, the histone deacetylase inhibitor entinostat is in phase III trials for patients with metastatic estrogen receptor-positive breast cancer. Predictors of sensitivity and resistance, however, remain unknown.MethodsA total of eight cell lines and nine mouse models of breast cancer were treated with entinostat. Luminal cell lines were treated with or without entinostat at their IC50 doses, and MMTV/Neu luminal mouse tumors were untreated or treated with entinostat until progression. We investigated these models using their gene expression profiling by microarray and copy number by arrayCGH. We also utilized the network-based DawnRank algorithm that integrates DNA and RNA data to identify driver genes of resistance. The impact of candidate drivers was investigated in The Cancer Genome Atlas and METABRIC breast cancer datasets.ResultsLuminal models displayed enhanced sensitivity to entinostat as compared to basal-like or claudin-low models. Both in vitro and in vivo luminal models showed significant downregulation of Myc gene signatures following entinostat treatment. Myc gene signatures became upregulated on tumor progression in vivo and overexpression of Myc conferred resistance to entinostat in vitro. Further examination of resistance mechanisms in MMTV/Neu tumors identified a portion of mouse chromosome 4 that had DNA copy number loss and low gene expression. Within this region, Jun was computationally identified to be a driver gene of resistance. Jun knockdown in cell lines resulted in upregulation of Myc signatures and made these lines more resistant to entinostat. Jun-deleted samples, found in 17–23% of luminal patients, had significantly higher Myc signature scores that predicted worse survival.ConclusionsEntinostat inhibited luminal breast cancer through Myc signaling, which was upregulated by Jun DNA loss to promote resistance to entinostat in our models. Jun DNA copy number loss, and/or high MYC signatures, might represent biomarkers for entinostat responsiveness in luminal breast cancer.
Highlights
Based on promising phase II data, the histone deacetylase inhibitor entinostat is in phase III trials for patients with metastatic estrogen receptor-positive breast cancer
To examine sensitivity in vitro, we identified the IC50 doses of entinostat for seven human breast cancer cell lines (Fig. 1a)
Given that sensitivity to entinostat was dependent on repression of Myc target genes and that resistance to entinostat was marked by Jun loss, we examined whether loss of c-Jun restored the molecular features of Myc activation
Summary
Based on promising phase II data, the histone deacetylase inhibitor entinostat is in phase III trials for patients with metastatic estrogen receptor-positive breast cancer. For postmenopausal women with metastatic ER-positive breast cancer, a randomized phase II trial of entinostat showed benefits in both progression-free and overall survival and the incidence of reported cardiac disorders was similar between entinostat and placebo arms [11]. With these promising results, entinostat received breakthrough designation from the Food and Drug Administration (FDA), and currently, a phase III registration trial E2112 (NCT02115282) is ongoing
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