The novel oleanolic acid derivative ZQL-4c modulates trastuzumab resistance in HER2+ breast cancer by inhibiting SCD-mediated lipid metabolism disorders.

Approximately 15% to 20% of patients with breast cancer are human epidermal growth factor 2 (HER2)-positive, and this type has a high recurrence rate. With the application of anti-HER2 drugs such as trastuzumab, the prognosis of patients with HER2-positive breast cancer has improved significantly. However, more than 30% of patients present with recurrence and distant metastasis due to drug resistance. It is important to develop new drugs to overcome trastuzumab resistance. Therefore, in collaboration with a research group at Dalian University of Technology, we synthesized ZQL-4c, a novel oleanolic acid (OA) derivative that was found to target the lipid metabolism reprogramming function of stearoyl-CoA desaturase (SCD), inducing lipotoxicity-mediated apoptosis. These findings provide an attractive future direction for the treatment of HER2-positive trastuzumab-resistant breast cancer.