Metabolism-dependent secondary effect of anti-MAPK cancer therapy on DNA repair [QuantSeq_BRAF]

The translation-dependent effect of amino acid bioavailability on the nature of proteins that cells express could have major consequences on their phenotype. We report that the intracellular concentration decrease of amino acids like aspartate and glutamate in a melanoma cell line exposed to anti-cancer MAPK inhibitors (MAPKi) triggers ribosomal peaks in mRNA regions enriched in codons corresponding to these amino acids and in the translation-dependent degradation of mRNAs encoding proteins enriched in these amino acids. Since aspartate- and glutamate-rich proteins are involved in cell proliferation and DNA repair, we propose that MAPKi surviving cells degrade aspartate and glutamate to generate energy which simultaneously decreases their needs through the downregulation of gene products involved in cell proliferation. Moreover, the expression level decrease of aspartate- and glutamate-rich proteins involved in DNA repair increases as a side effect the probability of DNA damages and consequently the emergence of mutated cells in response to MAPKi. QuanSeq data of A375 cells treated with MAPK inhibitors or DMSO for 18 hours then grown for 0, 1, 3 or 5 hours in a medium containing either DMSO, tryptolide (T), cycloheximid (CHX) or tryptolide and cycloheximid (TCHX). Cells grown for 0h corresponds to cell immediately harvested after DMSO, tryptolide, cycloheximid or tryptolide and cycloheximid treatment.