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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Triple-negative breast cancer (TNBC) is characterized by poor prognosis and metastasis.
• A specific cell-of-origin mRNA signature linked to TNBC progression involves overexpression of HDAC1, HDAC7, and ZNF92.
• Histone deacetylases (HDACs) and heat shock protein 90 (HSP90) are implicated in cancer development.

Purpose of the Study:

• To identify a therapeutic strategy targeting the TNBC cell-of-origin signature.
• To evaluate the synergistic effect of combining an HDAC inhibitor, Niclosamide, and an HSP90 inhibitor on TNBC and inflammatory breast carcinoma (IBC) cell lines.

Main Methods:

• Identification of a TNBC cell-of-origin mRNA signature.
• Treatment of TNBC and IBC cell lines with a combination of an HDAC inhibitor, Niclosamide, and Tanespimycin (HSP90 inhibitor).
• Assessment of drug concentrations for clinical relevance.

Main Results:

• The drug combination synergistically reduced proliferation in twelve tested TNBC cell lines.
• Four out of five IBC cell lines demonstrated sensitivity to the combination therapy.
• Effective drug concentrations were within or below clinically achievable doses.

Conclusions:

• The combination of HDAC inhibitors, Niclosamide, and HSP90 inhibitors exhibits significant synergistic activity against TNBC and IBC.
• Repurposing these clinically approved drugs may offer a novel therapeutic approach for TNBC and IBC treatment.