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

Although protein synthesis inhibitors are being evaluated as anti-cancer agents, the dynamics of mRNA translation in early tumorigenesis are still poorly understood. 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. Analysis of these eIF4A2-deleted tumors through a combination of multiplex imaging and spatial transcriptomics pointed to a rewiring of KRAS downstream pathways through enhanced MAP-kinase and reduced PI3K signalling. Consequently, these tumors may be eradicated by administration of a MEK inhibitor, in contrast to eIF4A2 positive lesions. Thus, dysregulated mRNA translation exposes a potential therapeutic vulnerability in KRAS-driven lung adenocarcinoma by forcing cancer cells to rely on MEK signalling.