ZSTK3744, a Novel Aryl Hydrocarbon Receptor Agonist, Exhibits Efficacy against Chemotherapy-Resistant Triple-Negative Breast Cancer.

[UNLABELLED] 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 limited by chemotherapy resistance, a substantial challenge in clinical management. The present study 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 parental 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 antitumor activity in vitro and in vivo. 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 acts 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.

[SIGNIFICANCE] ZSTK3744 was identified through screening for its cell growth-inhibitory activity on chemotherapy-resistant TNBC cells. ZSTK3744 exerts its activity through AhR. ZSTK3744 exhibits superior cell growth-inhibitory activity compared with other AhR agonists and demonstrates a favorable safety profile. Therefore, ZSTK3744 is a promising therapeutic agent for overcoming chemotherapy resistance in TNBC.