Repurposing Quetiapine as an Adjuvant Therapeutic Agent for Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) lacks actionable molecular targets, so treatment primarily relies on cytotoxic chemotherapy and radiotherapy, yet relapse, resistance, and metastasis still drives poor long-term survival. Dopamine signaling has recently been linked to tumor aggressiveness, and dopamine-receptor antagonists have shown preclinical benefit in other cancers. We therefore evaluated quetiapine (QTP), an FDA-approved DRD2/DRD3 antagonist, as a therapeutic adjunct in TNBC. SUM159-PT, BT-549, and MDA-MB-231 cells were treated with QTP alone or combined with radiation or standard agents (doxorubicin, paclitaxel, 5-fluorouracil). Clonogenic and mammosphere assays measured proliferative and self-renewal potential. Annexin V/propidium-iodide flow cytometry quantified apoptosis, and γ-H2AX immunofluorescence tracked DNA double-strand breaks and repair kinetics. Transwell assays assessed migration of untreated bulk cells and radiation-surviving subclones. QTP significantly reduced clonogenicity and self-renewal in all TNBC models tested, both alone and in combination with radiation or chemotherapy. In apoptosis assays, QTP treatment induced a marked increase in early and late apoptotic cell populations. QTP also promoted DNA double-strand break formation and delayed repair, as indicated by persistent γ-H2AX foci at 24 h after treatment. Additionally, QTP impaired the migratory capacity of both untreated and radiation-surviving cells. Combination treatments with QTP and doxorubicin produced synergistic effects, resulting in complete loss of colony-forming ability and mammosphere formation. The data presented support the repurposing of quetiapine as an adjuvant therapeutic agent alongside radiotherapy and/or chemotherapy in TNBC. By targeting apoptosis, DNA repair, and cancer cell migration, QTP offers a novel, multi-faceted approach to improve outcomes in this high-risk breast cancer subtype.