Beschreibung:
<jats:title>Abstract</jats:title><jats:p>Targeting mTORC1 is a highly promising strategy in cancer therapy. Suppression of mTORC1 activity leads to rapid dephosphorylation of eIF4E-binding proteins (4E-BP1–3) and subsequent inhibition of mRNA translation. However, how the different 4E-BPs affect translation during prolonged use of mTOR inhibitors is not known. Here we show that the expression of 4E-BP3, but not that of 4E-BP1 or 4E-BP2, is transcriptionally induced during prolonged mTORC1 inhibition <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic>. Mechanistically, our data reveal that 4E-BP3 expression is controlled by the transcription factor TFE3 through a <jats:italic>cis</jats:italic>-regulatory element in the <jats:italic>EIF4EBP3</jats:italic> gene promoter. CRISPR/Cas9-mediated <jats:italic>EIF4EBP3</jats:italic> gene disruption in human cancer cells mitigated the inhibition of translation and proliferation caused by prolonged treatment with mTOR inhibitors. Our findings show that 4E-BP3 is an important effector of mTORC1 and a robust predictive biomarker of therapeutic response to prolonged treatment with mTOR-targeting drugs in cancer.</jats:p>