Oncogene-dependent sloppiness in mRNA translation

mRNA translation is a highly conserved and tightly controlled mechanism for protein synthesis. Despite protein quality control mechanisms, amino acid shortage in melanoma induces aberrant proteins by ribosomal frameshifting. The extent and the underlying mechanisms related to this phenomenon are yet unknown. Here, we show that tryptophan depletion-induced ribosomal frameshifting is a widespread phenomenon in cancer. We termed this event sloppiness and strikingly observed its association with MAPK pathway hyperactivation. Sloppiness is stimulated by RAS activation in primary cells, suppressed by pharmacological inhibition of the oncogenic MAPK pathway in sloppy cells, and restored in cells with acquired resistance to MAPK pathway inhibition. Interestingly, sloppiness causes aberrant peptide presentation at the cell surface, allowing recognition and specific killing of drug-resistant cancer cells by T lymphocytes. Thus, while oncogenes empower cancer progression and aggressiveness, they also expose a vulnerability by provoking the production of aberrant peptides through sloppiness. [Display omitted] •Sloppiness is defined by ribosomal frameshifting upon tryptophan shortage•MAPK pathway hyperactivation links sloppiness to cancer•Sloppiness causes aberrant peptide presentation at the cell surface•Drug-resistant cancer cells remain sloppy and are targeted by T cells When amino acids are scarce, cancer cells are prone to produce aberrant protein. Here, Champagne et al. show that these errors result from the hyperactivation of oncogenic pathways. This cancer behavior represents a therapeutic opportunity by allowing T lymphocytes to recognize and kill resistant tumors.