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

Abstract

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.