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. Working model showing that AKT stabilizes SOX2 by phosphorylating T116 site. Phosphorylation by AKT restraints the binding and ubiquitinoylation of SOX2 by the UBR5 and STUB1, thus promoting SOX2 stability and tumorigenic activity. Targeting AKT by MK2206 inhibits T116 phosphorylation and promotes SOX2 ubiquitination pathway, which impairs SOX2 tumorigenic activity. A combined treatment with chemo reagent and AKT inhibitor could achieve better therapeutic effect for SOX2-positive OS.