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

Abstract

PurposeTriple-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 dopaminel1lreceptor antagonists have shown preclinical benefit in other cancers. We therefore evaluated quetiapine (QTP), an FDAl1lapproved DRD2/DRD3 antagonist, as a therapeutic adjunct in TNBC. MethodsSUM159l1lPT, BTl1l549, and MDAl1lMBl1l231 cells were treated with QTP alone or combined with radiation or standard agents (doxorubicin, paclitaxel, 5l1lfluorouracil). Clonogenic and mammosphere assays measured proliferative and selfl1lrenewal potential. Annexin V/propidiuml1liodide flow cytometry quantified apoptosis, and {gamma}l1lH2AX immunofluorescence tracked DNA doublel1lstrand breaks and repair kinetics. Transwell assays assessed migration of untreated bulk cells and radiationl1lsurviving subclones. ResultsQTP 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 {gamma}-H2AX foci at 24 hours post-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. ConclusionThe 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.