Cell-of-Origin Targeted Drug Repurposing for Triple-Negative and Inflammatory Breast Carcinoma with HDAC and HSP90 Inhibitors Combined with Niclosamide

SIMPLE SUMMARY: The human body is composed of hundreds of different normal cell types. Some of the important and unique features of these normal cell types are inherited by the cancer cells that arise from them. Indeed, the activities of the tumor gene mutations are constrained by this normal cell inheritance. For example, we previously found that the same oncogenes produce highly malignant tumors in some cell types but not in others. In this study, we demonstrate that this cell-of-origin difference can be used to develop cell-targeted therapies, a novel concept that differs from gene-targeted therapies. This cell-based approach guided us to a surprising discovery that a drug approved for treating tapeworm infestation in combination with an antibiotic derivative can significantly enhance the killing of breast cancer cells. Since these drugs are already approved for clinical use, it may be possible to repurpose them to treat breast cancer. ABSTRACT: We recently identified a cell-of-origin-specific mRNA signature associated with metastasis and poor outcome in triple-negative carcinoma (TNBC). This TNBC cell-of-origin signature is associated with the over-expression of histone deacetylases and zinc finger protein HDAC1, HDAC7, and ZNF92, respectively. Based on this signature, we discovered that the combination of three drugs (an HDAC inhibitor, an anti-helminthic Niclosamide, and an antibiotic Tanespimycin that inhibits HSP90) synergistically reduces the proliferation of the twelve tested TNBC cell lines. Additionally, we discovered that four out of five inflammatory breast carcinoma cell lines are sensitive to this combination. Significantly, the concentration of the drugs that are used in these experiments are within or below clinically achievable dose, and the synergistic activity only emerged when all three drugs were combined. Our results suggest that HDAC and HSP90 inhibitors combined with the tapeworm drug Niclosamide can achieve remarkably synergistic inhibition of TNBC and IBC. Since Niclosamide, HDAC, and HSP90 inhibitors were approved for clinical use for other cancer types, it may be possible to repurpose their combination for TNBC and IBC.