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

Although inhibitors of mRNA translation are being evaluated as anti-cancer agents, the dynamics of protein synthesis throughout tumour progression are still poorly understood. Here we assess how alterations in mRNA translation during early tumorigenesis affect tumour development in KRAS-driven lung adenocarcinoma (LuAd).

We deployed autochthonous mouse models of LuAd driven by oncogenic KRAS^G12D combined with moderate overexpression of MYC and simultaneously manipulated mRNA translation by deleting the mRNA helicases eIF4A1 and eIF4A2 or by administering pharmacological inhibitors of protein synthesis, such as rapamycin. This permits synchronous assessment of LuAd initiation and progression in vivo and is amenable to parallel ex vivo culture of tumour-derived cells for detailed analysis of protein synthesis (using ribosome footprinting) and metabolic landscapes. These approaches also allowed us to perform multiplex imaging and spatial transcriptomics to characterise tumour formation in altered mRNA translation conditions and to compare results obtained in mice against the Lattice-A cohort of non-small cell lung cancer (NSCLC) patients.

Deletion of the mRNA-translation repressor, eIF4A2 in KRAS-driven LuAd 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 secretory protein synthesis landscape delays tumorigenesis and leads to the appearance of clusters of non-proliferative, p21-positive KRAS^G12D-expressing cells in the lung. Consistently, reduction of mRNA translation with rapamycin in Eif4a2-deleted tumours suppresses senescence and restores tumorigenesis. Importantly, some Eif4a2 knockout cells overcome senescence to form tumours that exhibit enhanced MAP-kinase signalling and, in contrast to eIF4A2^+/+ lesions, these were eradicated by administration of a MEK inhibitor. Consistently, MAP-kinase signalling was significantly increased in human NSCLC expressing low levels of eIF4A2.

Our study highlights that restraint of mRNA translation by eIF4A2 is critical in the early-stages of KRAS-driven LuAd to allow bypass of oncogene-induced senescence and tumour progression. Importantly, because tumours with dysregulated mRNA translation rely heavily on MAP-kinase signalling they are exquisitely sensitive to MEK inhibition, and this indicates the possibility that low expression of eIF4A2 could be used to identify potential responders to MEK inhibitors in clinical trials.