eIF4A1 Inhibitor Suppresses Hyperactive mTOR-Associated Tumors by Inducing Necroptosis and G2/M Arrest

Aberrantly activated mechanistic target of rapamycin (mTOR) signaling pathway stimulates translation initiation/protein synthesis and eventually causes tumors. Targeting these processes thus holds potential for treating mTOR-associated diseases. We tested the potential of eFT226, a sequence-selective inhibitor of eIF4A-mediated translation, in the treatment of mTOR hyperactive cells caused by the deletion of tuberous sclerosis complex 1/2 (TSC1/2) or phosphatase and TENsin homology (PTEN). eFT226 preferentially inhibited the proliferation of Tsc2- and Pten-deficient cells by inducing necroptosis and G2/M phase arrest. In addition, eFT226 blocked the development of TSC2-deficient tumors. The translation initiation inhibitor is thus a promising regimen for the treatment of hyperactive mTOR-mediated tumors.

Automated summary

The aberrant activation of the mTOR signaling pathway can lead to tumor growth by stimulating translation initiation and protein synthesis. This study investigated the potential of eFT226, a selective inhibitor of eIF4A-mediated translation, in treating mTOR hyperactive cells caused by the deletion of TSC1/2 or PTEN. Results showed that eFT226 effectively inhibited the proliferation of Tsc2- and Pten-deficient cells by inducing necroptosis and G2/M phase arrest. Additionally, eFT226 blocked the development of TSC2-deficient tumors. Overall, these findings suggest that eFT226, as a translation initiation inhibitor, holds promise in the treatment of hyperactive mTOR-mediated tumors.