Increased mRNA translation delays tumor initiation and exposes a therapeutic vulnerability in lung cancer

We report that deletion of the mRNA-translation repressor, eIF4A2 in early KRAS-driven lung adenocarcinoma leads to a dysregulated protein synthesis landscape characterised by a strongly upregulated secretome, enlarged secretory compartments, increased oxidative metabolism and acquisition of senescence-like characteristics.

Paradoxically, this overdriven protein synthesis landscape delays tumorigenesis and leads to appearance of clusters of non-proliferative, p21-positive KRAS-expressing cells in the lung. Administration of rapamycin to reduce mRNA translation, suppresses senescence and restores tumorigenesis following eIF4A2 deletion. Importantly, some eIF4A2 deleted cells overcome senescence to form tumors that growth aggressively.