Abstract B070: Metformin enhances alpelisib sensitivity in HER2+ breast cancer by suppressing cancer stemness and oncogenic signaling

Abstract Alpelisib, a PIK3CA-targeting agent, is currently used for HR+/HER2- breast cancer, with HER2+ breast cancer less studied. A major side-effect of alpelisib that compromises its application is hyperglycemia. This study investigated the effects of combining alpelisib with metformin in HER2-overexpressing SK-BR-3 and BT-474 breast cancer. We found that while alpelisib alone inhibited cell proliferation, the combination with metformin induced a significant synergistic effect, as demonstrated by combination index analysis. The combination treatment enhanced inhibition of cell proliferation and colony formation, increased cell cycle arrest, and reduced cancer stem cell properties. Specifically, ALDH1+ populations in SK-BR-3 cells and tumorsphere formation in BT-474 cells were significantly reduced compared to either treatment alone. Mechanistically, the combination therapy downregulated key signaling pathways, including receptor tyrosine kinase and Wnt, by reducing protein levels of phosphorylated or active forms of p-Akt, p-Stat3, c-Myc, p-erbB2, p-ERK1/2, and active β-catenin. These results demonstrate that alpelisib exhibits potent anti-tumor activity in HER2+ breast cancer, which is significantly enhanced by metformin. Importantly, metformin’s dual role in enhancing anti-tumor effects and mitigating hyperglycemia highlights its potential to broaden the applicability of alpelisib in breast cancer treatment, which provides a strong rationale for further preclinical and clinical exploration of this combination therapy. Citation Format: Xiaohe Yang, Yujie Shi, Peijia Niu, Qiong Cheng, Lexia Chen, Yahan Weng. Metformin enhances alpelisib sensitivity in HER2+ breast cancer by suppressing cancer stemness and oncogenic signaling [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B070.