The SGK3/GSK3β/β-catenin signaling promotes breast cancer stemness and confers resistance to alpelisib therapy.

Drug resistance is the leading cause of death in patients with advanced tumors. Alpelisib, a selective PIK3CA inhibitor, has been recently approved for treating advanced breast cancer. However, drug resistance is inevitable, and the mechanisms behind alpelisib-associated resistance remain elusive. To address this problem, we established an alpelisib-resistant breast cancer cell model and confirmed that the resistant cells exhibited enhanced abilities in colony formation, migration, anti-apoptosis, spheroidization, tumor formation and metastasis. Further analysis revealed that SGK3 was significantly upregulated in alpelisib-resistant cells, which was strongly associated with tumor stemness. Additionally, we observed that SGK3 promoted tumor cell stemness by activating GSK3β/β-catenin signaling pathway, leading to the resistance to alpelisib in breast cancer. Finally, we demonstrated that SGK3 inhibitor could restore the sensitivity of resistant cells to alpelisib. Collectively, these findings suggest that SGK3 could be a novel therapeutic target for breast cancer patients who developed resistance to alpelisib.