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Dasatinib Inhibits Basal B Breast Cancer Through ETS1-Mediated Extracellular Matrix Remodeling
Xinyu Guo1,2, Heng Sun1,2,3, Feng Yu4
1Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR, China.
Abstract:
Background/Objectives: Developing effective therapies for patients with triple-negative breast cancer (TNBC) remains an urgent clinical priority. Compared with other subtypes, the basal B type of TNBC exhibits a less differentiated and mesenchymal-like phenotype that models highly invasive and metastatic breast malignancies. To target metastatic TNBC, our current study sought to identify effective therapeutic drugs and the underlying mechanisms. Methods: A systematic screening of 140 FDA-approved drugs was conducted for repurposing using live-cell imaging-based wound-healing assays. Candidate efficacy was validated by in vitro transwell invasion assays, in vivo allograft/xenograft models, and ex vivo three-dimensional air-liquid interface (ALI) and patient-derived organoid (PDO) cultures. Results: Dasatinib emerged as a promising anti-cancer agent in aggressive TNBC, particularly in the basal B type, with high ETS proto-oncogene 1 (ETS1) expression. Mechanistically, dasatinib disrupts the actin cytoskeleton, impairing cell motility and migration while concurrently suppressing the expression of ETS1 and matrix metalloproteinase-3 (MMP3) to remodel the extracellular matrix (ECM) and inhibit invasion. Moreover, the combination of dasatinib with an anti-programmed cell death protein-1 (PD-1) antibody represents a potential therapeutic strategy. Conclusions: These findings highlight dasatinib as a potential therapeutic option for metastatic TNBC and suggest that selecting patients with high ETS1 expression may optimize treatment response.
Insights
Dasatinib shows promise in treating aggressive triple-negative breast cancer (TNBC), especially the basal B subtype. This drug inhibits cancer cell migration and invasion by targeting ETS proto-oncogene 1 (ETS1) and matrix metalloproteinase-3 (MMP3).
Area of Science:
- Oncology
- Drug Discovery
- Cancer Metastasis
Background:
- Triple-negative breast cancer (TNBC), particularly basal B type, is highly invasive and metastatic.
- Effective therapies for metastatic TNBC are urgently needed.
- Understanding TNBC's underlying mechanisms is crucial for developing targeted treatments.
Purpose of the Study:
- To identify effective therapeutic drugs for metastatic TNBC through drug repurposing.
- To elucidate the mechanisms by which potential drugs inhibit TNBC invasion and metastasis.
- To evaluate dasatinib as a therapeutic agent for aggressive TNBC.
Main Methods:
- Systematic screening of 140 FDA-approved drugs using live-cell imaging wound-healing assays.
- Validation of drug efficacy through in vitro invasion assays, in vivo models, and ex vivo organoid cultures.
- Analysis of dasatinib's molecular mechanisms, including effects on the actin cytoskeleton, ETS1, and MMP3 expression.
Main Results:
- Dasatinib demonstrated significant anti-cancer activity in aggressive TNBC, especially basal B type with high ETS proto-oncogene 1 (ETS1) expression.
- Dasatinib disrupts the actin cytoskeleton, reduces cell motility, and suppresses ETS1 and matrix metalloproteinase-3 (MMP3) expression, inhibiting invasion.
- A combination therapy of dasatinib with an anti-programmed cell death protein-1 (PD-1) antibody showed potential.
Conclusions:
- Dasatinib is a potential therapeutic option for metastatic TNBC.
- Targeting patients with high ETS1 expression may optimize dasatinib treatment response.
- Further research into combination therapies, including with PD-1 inhibitors, is warranted.
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