Pharmacological screening and transcriptomic functional analyses identify a synergistic interaction between dasatinib...

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Triple-negative breast cancer (TNBC) lacks targeted therapies, necessitating the identification of novel druggable vulnerabilities.
• Gene set enrichment analysis (GSEA) and compound screening are key strategies for discovering new therapeutic combinations.

Purpose of the Study:

• To identify and evaluate synergistic drug combinations for treating triple-negative breast cancer.
• To investigate the mechanism of action of promising drug combinations.

Main Methods:

• Utilized GSEA with multiple datasets (GSE21422, GSE26910, GSE3744, GSE65194, GSE42568) to identify therapeutic targets.
• Screened over 35 compounds and evaluated combinations using MTT assays, semi-solid media studies, and Chou and Talalay algorithm for synergy.
• Performed flow cytometry and biochemical assays to elucidate the mechanism of action, including apoptosis and cell cycle analysis.

Main Results:

• The combination of dasatinib and olaparib demonstrated significant synergy in TNBC cell lines (MDAMB-231, BT549, HS-578T, HCC3153) and a broader panel of 18 solid tumor cell lines.
• This combination induced caspase-dependent apoptosis and exhibited pleiotropic cell cycle effects: dasatinib caused G0/G1 arrest, while olaparib induced G2/M arrest.
• Dasatinib inhibited pChk1 and increased DNA damage (pH2AX), whereas olaparib elevated pH3, indicating distinct molecular impacts.

Conclusions:

• Dasatinib and olaparib combination represents a potent synergistic therapeutic strategy for triple-negative breast cancer.
• The observed synergy involves inducing apoptosis and distinct cell cycle arrests, offering a novel approach for TNBC treatment.
• This combination also showed particular synergism in ovarian cancer, suggesting broader applicability in solid tumors.