Novel oleanolic acid derivative ZQL-4c as a target for SCD to modulate lipid metabolism reprogramming to overcome trastuzumab resistance in HER2 positive breast cancer.

e13009 Background: Approximately 15% to 20% of patients with breast cancer are characterized as Human epidermal growth factor2 (HER2) positive with a high recurrence rate and a poor survival outcome. With the development and 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 still experience treatment failure, recurrence, and distant metastasis due to drug resistance. It is therefore important to develop new drugs to overcome trastuzumab resistance and investigate the precise mechanism. Oleanolic acid (OA), one of the most common pentacyclic triterpenoids, has been shown to have significant benefits in treating tumors. Still, its clinical application is limited due to its poor bioavailability and target uncertainty. Methods: We synthesized ZQL-4c, a novel derivative of oleanolic acid with anti-tumor activity, which can target the reprogramming function of lipid metabolism of Stearoyl-CoA desaturase (SCD) to overcome resistance to trastuzumab in HER2 positive breast cancer, along with a panel from Dalian University of Technology. Results: After exploring the anti-tumor effects of ZQL-4c in trastuzumab-resistant tumors, we assessed overcoming resistance through the combination of ZQL-4c and trastuzumab. To further identify the SCD target of ZQL-4c, we used multi-omics association and molecular docking technology and established drug-resistant tumor models with SCD overexpression in vivo and ex vivo. We found that targeting SCD could inhibit de novo lipid synthesis, thus inducing lipotoxicity-mediated apoptosis and exerting the effect of overcoming resistance to trastuzumab. Conclusions: In summary, our observations that the novel oleanolic acid derivative ZQL-4c inhibits apoptosis induced by lipotoxicity by targeting SCD provides an attractive future direction for treating HER2-positive trastuzumab-resistant breast cancer.