Imatinib revives the therapeutic potential of metformin on ewing sarcoma by attenuating tumor hypoxic response and inhibiting convergent signaling pathways

Highlights
- A drug repositioning and combination screening identified seven synergistic drug combinations in inhibiting the viability of Ewing sarcoma cell lines under hypoxia.
- The imatinib and metformin combination regimen has potent synergistic anti-tumor effect in Ewing sarcoma in vitro and in vivo models.
- This combination suppresses dominant mechanisms in Ewing sarcoma including the key EWS-FLI1 downstream targets that are convergent into the PI3K/AKT/mTOR signaling pathway.
- The drug combination-related 48 gene signature showed significant correlation with clinical outcomes in Ewing sarcoma, sarcoma, GBM, stage III-IV ovarian cancer and early stage breast cancer cohorts.