ZSTK3744, a Novel Aryl Hydrocarbon Receptor Agonist, Overcomes Chemotherapy Resistance in Triple-Negative Breast Cancer [microarray]

ABSTRACT: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by a poor prognosis owing to the lack of therapeutic targets, including hormone receptors and HER2. Systemic chemotherapy remains the primary treatment option; however, its efficacy is frequently limited by chemotherapy resistance, a substantial challenge in clinical management. In the present study, we aimed to develop a novel anticancer drug that overcomes chemotherapy resistance in TNBC. First, chemotherapy-resistant MDA-MB-468 cells derived from TNBC were developed via long-term exposure to adriamycin or paclitaxel. Compared with wild-type cells, these resistant cells exhibited reduced sensitivity to paclitaxel, adriamycin, and eribulin in the viability assays. Various compounds were screened for their cell growth-inhibitory activity against these resistant cells to identify novel therapeutic agents; ZSTK3744 was a promising candidate and showed significant anti-tumor activity in vitro and in vivo. Mechanistically, ZSTK3744 upregulated CYP1A1, CYP1B1, and TIPARP expression in MDA-MB-468 cells but exhibited no cell growth-inhibitory activity in aryl hydrocarbon receptor (AhR) knockout cells, indicating that ZSTK3744 act as an AhR agonist. Notably, ZSTK3744 demonstrated superior tumor inhibition and lower pulmonary toxicity in ex vivo and in vivo models than other AhR agonists. These results suggest that ZSTK3744 combines robust cell growth-inhibitory activity with a favorable safety profile. In conclusion, ZSTK3744 is a promising candidate for overcoming chemotherapy resistance in TNBC, addressing the urgent need for more effective treatment options for this aggressive cancer subtype. This study represents the first demonstration of the anti-tumor activity of an AhR agonist on chemotherapy-resistant TNBC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305009 | GEO | 2025/12/31

REPOSITORIES: GEO