Targeting AKT as a promising strategy for SOX2-positive, chemoresistant osteosarcoma

Abstract Osteosarcoma (OS) is the most prevalent type of primary malignant bone cancer and currently lacks effective targeted treatments. Increasing evidence indicates that SOX2 overexpression is a primary driver of OS. By screening a small-molecule kinase inhibitor library, we identified AKT as a kinase essential for robust SOX2 expression in OS cells. AKT was found to be frequently overexpressed in OS and positively correlated with SOX2 protein levels. We demonstrated that AKT has no effect on SOX2 transcription but promotes SOX2 protein stability. Mechanistically, AKT binds to and phosphorylates SOX2 at T116, preventing SOX2 ubiquitination and proteasome-dependent degradation by ubiquitin E3 ligases UBR5 and STUB1. Moreover, we found that AKT-SOX2 axis is a significant modulator of cancer stemness and chemoresistance and that the combination of AKT inhibitor MK2206 and cisplatin resulted in a synergistic and potent inhibition of OS tumor growth in the PDX model. In conclusion, we identified a critical role for AKT in promoting SOX2 overexpression, tumor stemness, and chemoresistance in OS, and provided evidence that targeting AKT combined with chemotherapy may hold promise for treating refractory OS.