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Identification of Nuclear Export Inhibitor-Based Combination Therapies in Preclinical Models of Triple-Negative Breast Cancer

ABSTRACT: Identification of Nuclear Export Inhibitor-Based Combination Therapies in Preclinical Models of Triple-Negative Breast Cancer

PROVIDER: PRJNA729731 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14522400_1.fastq.gz	Fastqsanger.gz
	SRR14522400_2.fastq.gz	Fastqsanger.gz
	SRR14522401_1.fastq.gz	Fastqsanger.gz
	SRR14522401_2.fastq.gz	Fastqsanger.gz
	SRR14522402_1.fastq.gz	Fastqsanger.gz

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Identification of Nuclear Export Inhibitor-Based Combination Therapies in Preclinical Models of Triple-Negative Breast Cancer

Project description:An estimated 284,000 Americans will be diagnosed with breast cancer in 2021. Of these individuals, 15-20% will be diagnosed with basal-like triple-negative breast cancer (TNBC), which is known to be highly metastatic. Chemotherapy is standard of care for TNBC patients, but acquired chemoresistance is a common clinical problem. There is currently a lack of alternative, targeted treatment strategies for TNBC; this study sought to identify novel therapeutic combinations to treat basal-like TNBCs. For these studies, a set of four human basal-like TNBC cell lines was utilized to determine the cytotoxicity profile of 1,363 unique clinically-used drugs. Ten promising therapeutic candidates were identified, and synergism studies were performed in vitro. Two drug combinations that included KPT-330, an XPO1 inhibitor, were synergistic in all four cell lines. In vivo testing of four basal-like patient-derived xenografts identified a combination, KPT-330 and GSK2126458 (a PI3K/mTOR inhibitor), that decreased tumor burden in mice significantly more than monotherapy with either single agent. Bulk and single-cell RNA-sequencing, immunohistochemical studies, and analysis of published genomic datasets found that XPO1 was abundantly expressed in human basal-like TNBC cell lines, patient-derived xenografts, and patient tumor samples; within basal-like patients, XPO1 overexpression was associated with greater rates of metastases. These studies identify a promising new combination therapy for patients with basal-like TNBC.

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